NR1H2 and NR1H3-mediated signaling (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="NR1H2 and NR1H3-mediated signaling" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">The liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily and function as ligand-activated transcription factors. The natural ligands of NR1H2 and NR1H3 are oxysterols (e.g., 24(S),25-epoxycholesterol, 24(S)-hydroxycholesterol (OH), 25-OH, and 27-OH) that are produced endogenously by enzymatic reactions, by reactive oxygen species (ROS)-dependent oxidation of cholesterol and by the alimentary processes (reviewed in:Jakobsson T et al. 2012; Huang C 2014; Komati R et al. 2017). It has been shown that these oxysterols bind directly to the ligand-binding domain of LXRs with Kd values ranging from 0.1 to 0.4 microM. 24(S), 25-epoxycholesterol was found to be the most potent endogenous agonist (Janowski BA et al. 1999). NR1H3 (LXRα) and NR1H2 (LXRβ) showed similar affinities for these compounds (Janowski BA et al. 1999). In physiological conditions, oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors to alter gene expression and protect the cells from cholesterol overload via: (1) inhibiting intestinal cholesterol absorption; (2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1: (3) activating the conversion of cholesterol to bile acids in the liver; and (4) activating biliary cholesterol and bile acid excretion (reviewed in: Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J &amp; Rydén M 2012; Edwards PA et al. 2002; Zelcer N &amp; Tontonoz P 2006; Zhao C &amp; Dahlman-Wright K 2010). In addition, LXR agonists enhance de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and hepatic steatosis (Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J &amp; Rydén M 2012). In addition to their function in lipid metabolism, NR1H2,3 have also been found to modulate immune and inflammatory responses in macrophages (Zelcer N &amp; Tontonoz P 2006). The NR1H2 and NR1H3 molecules can be viewed as having four functional domains: (1) an amino-terminal ligand-independent activation function domain (AF-1), which may stimulate transcription in the absence of ligand; (2) a DNA-binding domain (DBD) containing two zinc fingers; (3) a hydrophobic ligand-binding domain (LBD) required for ligand binding and receptor dimerization; and, (4) a carboxy-terminal ligand-dependent transactivation sequence (also referred to as the activation function-2 (AF-2) domain) that stimulates transcription in response to ligand binding (Robinson-Rechavi M et al. 2003; Jakobsson T et al. 2012; Färnegardh M et al. 2003; Lin CY &amp; Gustafsson JA 2015). Although both NR1H3 and NR1H2 are activated by the same ligands and are structurally similar, their tissue expression profiles are very different. NR1H3 is selectively expressed in specific tissues and cell types, such as the liver, intestine, adrenal gland, adipose tissue and macrophages, whereas NR1H2 is ubiquitously expressed (Nishimura M et al. 2004; Bookout AL et al. 2006). Upon activation NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF &amp; Gustafsson JA 1997). An inverted repeat of the same consensus sequence with no spacer region(IR-0) and an inverted repeat of the same consensus sequence separated by a 1 bp spacer (IR-1) have also been shown to mediate LXR transactivation (Mak PA et al. 2002, Landrier JF et al. 2003). NR1H3 and NR1H2 have been shown to regulate gene expression via LXREs in the promoter regions of their target genes such as UDP glucuronosyltransferase 1 family, polypeptide A3 (UGT1A3) (Verreault M et al. 2006), fatty acid synthase (FAS) (Joseph SB et al. 2002a), carbohydrate response element binding protein (ChREBP, also known as MLX-interacting protein-like or MLXIPL) (Cha JY &amp; Repa JJ 2007) and phospholipid transfer protein (PLTP) (Mak PA et al. 2002). LXREs have also been reported to be present in introns of target genes such as the ATP-binding cassette transporter G1 (ABCG1) (Sabol SL et al. 2005). NR1H3 has been shown to activate gene expression via the FXR-responsive element found in the proximal promoter of the human ileal bile acid-binding protein (FABP6) (Landrier JF et al. 2003). The NR1H2,3:RXR heterodimers are permissive, in that they can be activated by ligands for either NR1H2,3 (LXR) or RXR (Willy PJ et al. 1995). 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<DataNode TextLabel="NR1H2 " GraphId="a978c" Type="Protein" GroupRef="b2228"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024349" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="240.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55055" /> </DataNode> <DataNode TextLabel="KDM4A " GraphId="a993f" Type="Protein" GroupRef="fbd4e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024378" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="100.0" CenterY="3405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75164" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="a9bc7" Type="Metabolite" GroupRef="bd303"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute 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TextLabel="24(S),25-epoxycholesterol " GraphId="ab1c8" Type="Metabolite" GroupRef="e0019"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029599" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="380.0" CenterY="3265.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:41633" /> </DataNode> <DataNode TextLabel="APOC1" GraphId="ab38f" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2114.5" CenterY="1342.0" Width="51.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P02654" /> </DataNode> <DataNode TextLabel="NCOA1 " GraphId="ab443" Type="Protein" GroupRef="e0019"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029599" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" 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Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="47" /> <Graphics CenterX="1360.0" CenterY="2885.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="ada5c" Type="Protein" GroupRef="c897c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9657821" /> <Attribute Key="copies_num" Value="63" /> <Graphics CenterX="2060.0" CenterY="3245.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="27-hydroxycholesterol " GraphId="ade76" Type="Metabolite" GroupRef="ba53e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024330" /> <Attribute Key="copies_num" Value="13" /> <Graphics CenterX="380.0" CenterY="3065.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:76591" /> </DataNode> <DataNode TextLabel="PCK1 gene" GraphId="adfbb" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1548.0" CenterY="2223.5" Width="72.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000124253" /> </DataNode> <DataNode TextLabel="miR-26A RISC " GraphId="ae326" GroupRef="a6289"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9011867" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3165.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-2318737" /> </DataNode> <DataNode TextLabel="NR1H2,3:RXR:NR1H2,3&#xA;ligand:FABP6 gene" GraphId="ae3bd" Type="Complex"> <Attribute 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ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="ABCA1gene:NR1H2,3:RXR:NR1H2,3 ligands:NCOR:GPS2:TBL1:HDAC3" GraphId="ae611" Type="Complex"> <BiopaxRef>eaa</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="764.5" CenterY="402.0" Width="127.0" Height="64.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9024368" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="ae7d3" Type="Metabolite" GroupRef="d1bd1"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9631294" /> <Attribute Key="copies_num" Value="59" /> <Graphics CenterX="1920.0" CenterY="2805.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="HDAC3 " GraphId="ae932" Type="Protein" GroupRef="fdd70"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024373" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="2765.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15379" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="af116" Type="Protein" GroupRef="c897c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9657821" /> <Attribute Key="copies_num" Value="32" /> <Graphics CenterX="2060.0" CenterY="3185.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="af4d8" Type="Metabolite" GroupRef="d0c4b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035197" /> <Attribute Key="copies_num" Value="23" /> <Graphics CenterX="660.0" CenterY="3145.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="PLTP" GraphId="afd72" Type="Complex"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2101.0" CenterY="997.0" Width="36.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-194227" /> </DataNode> <DataNode TextLabel="27-hydroxycholesterol " GraphId="afe8e" Type="Metabolite" GroupRef="bd303"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-ALL-9024383" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2885.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:76591" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="aff92" Type="Metabolite" GroupRef="d0c4b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035197" /> <Attribute Key="copies_num" Value="23" /> <Graphics CenterX="660.0" CenterY="3105.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="ABCA1 gene " GraphId="affb9" Type="Protein" GroupRef="b2228"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024349" /> <Attribute Key="copies_num" Value="9" /> <Graphics CenterX="240.0" CenterY="2865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000165029" /> </DataNode> <DataNode TextLabel="24(S),25-epoxycholesterol " GraphId="b0229" Type="Metabolite" GroupRef="b4a91"> <Attribute 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CenterY="3265.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="b08c9" Type="Protein" GroupRef="ee612"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029543" /> <Attribute Key="copies_num" Value="19" /> <Graphics CenterX="520.0" CenterY="3085.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="NR1H2 " GraphId="b08f7" Type="Protein" GroupRef="ecbc7"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028535" /> <Attribute Key="copies_num" Value="20" /> <Graphics CenterX="1080.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55055" /> </DataNode> <DataNode 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<DataNode TextLabel="KDM1B " GraphId="ba76e" Type="Protein" GroupRef="e4d65"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024371" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8NB78" /> </DataNode> <DataNode TextLabel="PLTP-1 " GraphId="ba7e8" Type="Protein" GroupRef="eb35e"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-194227" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55058-1" /> </DataNode> <DataNode TextLabel="APOC2 gene" GraphId="bae93" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1503.5" CenterY="1467.5" 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<Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3105.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENST00000339728" /> </DataNode> <DataNode TextLabel="ANGPTL3 gene " GraphId="bcb70" Type="Protein" GroupRef="c897c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9657821" /> <Attribute Key="copies_num" Value="63" /> <Graphics CenterX="2060.0" CenterY="3425.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000132855" /> </DataNode> <DataNode TextLabel="NR1H2:RXRA" GraphId="bd085" Type="Complex"> <BiopaxRef>fcd</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1937.5" CenterY="495.0" Width="85.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9619754" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="bd207" Type="Protein" GroupRef="f725a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9619754" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3145.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="NR1H3 gene" GraphId="bd785" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1475.0" CenterY="1162.5" Width="82.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000025434" /> </DataNode> <DataNode TextLabel="EP300 " GraphId="bdb12" Type="Protein" GroupRef="b4a91"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029520" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="2665.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q09472" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="bde26" Type="Metabolite" GroupRef="fca82"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="47" /> <Graphics CenterX="1360.0" CenterY="2925.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="be6f9" Type="Protein" GroupRef="fca82"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="24" /> <Graphics CenterX="1360.0" CenterY="2745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="be773" Type="Protein" GroupRef="b4a91"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029520" /> <Attribute Key="copies_num" Value="9" /> <Graphics CenterX="520.0" CenterY="2745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="be858" Type="Metabolite" GroupRef="e51cc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035175" /> <Attribute Key="copies_num" Value="35" /> <Graphics CenterX="940.0" CenterY="3105.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="NR1H2 " GraphId="bec2e" Type="Protein" GroupRef="ec6ff"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9031523" /> <Attribute Key="copies_num" Value="14" /> <Graphics CenterX="800.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55055" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="bf10a" Type="Protein" GroupRef="ecbc7"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028535" /> <Attribute Key="copies_num" Value="39" /> <Graphics CenterX="1080.0" CenterY="2725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="bf3d6" Type="Protein" GroupRef="be5fb"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028528" /> <Attribute Key="copies_num" Value="21" /> <Graphics CenterX="1080.0" CenterY="3025.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" 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</DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="c1450" Type="Metabolite" GroupRef="c0946"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035164" /> <Attribute Key="copies_num" Value="33" /> <Graphics CenterX="940.0" CenterY="2845.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="c149b" Type="Protein" GroupRef="c8a5b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623370" /> <Attribute Key="copies_num" Value="27" /> <Graphics CenterX="1640.0" CenterY="3285.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="24(S),25-epoxycholesterol " GraphId="c15fd" Type="Metabolite" GroupRef="f5992"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9618399" /> <Attribute Key="copies_num" Value="51" /> <Graphics CenterX="1640.0" CenterY="2865.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:41633" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="c19c0" Type="Protein" GroupRef="ba53e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024330" /> <Attribute Key="copies_num" Value="13" /> <Graphics CenterX="380.0" CenterY="2885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="c1bf3" Type="Metabolite" GroupRef="fbd4e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024378" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="100.0" CenterY="3245.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="NCOR2 " GraphId="c1d0b" Type="Protein" GroupRef="fdd70"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024373" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y618" /> </DataNode> <DataNode TextLabel="NCOR1 " GraphId="c1fb1" Type="Protein" GroupRef="f8813"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024368" /> <Attribute Key="copies_num" Value="11" /> <Graphics CenterX="240.0" CenterY="3005.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75376" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c2227" Type="Metabolite" GroupRef="bd303"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-ALL-9024383" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2805.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="c225f" Type="Protein" GroupRef="b6152"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035153" /> <Attribute Key="copies_num" Value="16" /> <Graphics CenterX="800.0" CenterY="3305.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="MOV10 " GraphId="c226d" Type="Protein" GroupRef="da881"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9038541" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="1500.0" CenterY="2725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HCE1" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c2677" Type="Metabolite" GroupRef="ecbc7"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028535" /> <Attribute Key="copies_num" Value="39" /> <Graphics CenterX="1080.0" CenterY="2805.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="c28eb" Type="Metabolite" GroupRef="ec392"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028534" /> <Attribute Key="copies_num" Value="37" /> <Graphics CenterX="940.0" CenterY="3445.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="c2f91" Type="Protein" GroupRef="c897c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9657821" /> <Attribute Key="copies_num" Value="32" /> <Graphics CenterX="2060.0" CenterY="3225.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="ABCA1 gene " GraphId="c3c58" Type="Protein" GroupRef="e0019"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029599" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="380.0" CenterY="3225.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000165029" /> </DataNode> <DataNode TextLabel="NCOA1 " GraphId="c3dfa" Type="Protein" GroupRef="e64e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035268" /> <Attribute Key="copies_num" Value="49" /> <Graphics CenterX="1360.0" CenterY="3305.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15788" /> </DataNode> <DataNode TextLabel="ABCA1 mRNA:miR-26&#xA;RISC" GraphId="c3e9f" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1930.0" CenterY="323.0" Width="114.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9618481" /> </DataNode> <DataNode TextLabel="NR1H2,3:RXR" GraphId="c424d" Type="Complex"> <BiopaxRef>ac1</BiopaxRef> <BiopaxRef>fcd</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="905.5" CenterY="887.0" Width="87.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9024381" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="c433d" Type="Protein" GroupRef="e0019"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029599" /> <Attribute Key="copies_num" Value="8" /> <Graphics CenterX="380.0" CenterY="3145.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="c4459" Type="Protein" GroupRef="d0c4b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035197" /> <Attribute Key="copies_num" Value="23" /> <Graphics CenterX="660.0" CenterY="3025.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c5072" Type="Metabolite" GroupRef="f5992"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9618399" /> <Attribute Key="copies_num" Value="51" /> <Graphics CenterX="1640.0" CenterY="2905.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="APOC1 gene" GraphId="c5f19" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1502.5" CenterY="1373.5" Width="83.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000130208" /> </DataNode> <DataNode TextLabel="24(S),25-epoxycholesterol " GraphId="c6183" Type="Metabolite" GroupRef="c0946"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035164" /> <Attribute Key="copies_num" Value="33" /> <Graphics CenterX="940.0" CenterY="2765.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:41633" /> </DataNode> <DataNode TextLabel="UGT1A3 gene " GraphId="c64c8" Type="Protein" GroupRef="fca82"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="47" /> <Graphics CenterX="1360.0" CenterY="2985.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000243135" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="c66d4" Type="Protein" GroupRef="d1bd1"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9631294" /> <Attribute Key="copies_num" Value="30" /> <Graphics CenterX="1920.0" CenterY="2665.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="c6795" Type="Protein" GroupRef="c0946"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035164" /> <Attribute Key="copies_num" Value="33" /> <Graphics CenterX="940.0" CenterY="2725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="miR-26B RISC " GraphId="c6a8e" GroupRef="dcd9a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9618481" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3085.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-9011856" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="c6fa8" Type="Metabolite" GroupRef="b6152"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035153" /> <Attribute Key="copies_num" Value="31" /> <Graphics CenterX="800.0" CenterY="3445.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="UGT1A3&#xA;gene:NR1H2,3:RXR:NR1H2,3 ligand:NCOA1" GraphId="c70a8" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1109.5" CenterY="2504.0" Width="129.0" Height="64.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9035268" /> </DataNode> <DataNode TextLabel="ANGPTL3" GraphId="c77f5" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2116.0" CenterY="2418.0" Width="60.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y5C1" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c7805" Type="Metabolite" GroupRef="f828c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9031524" /> <Attribute Key="copies_num" Value="25" /> <Graphics CenterX="660.0" CenterY="3405.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c78ff" Type="Metabolite" GroupRef="c0946"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035164" /> <Attribute Key="copies_num" Value="33" /> <Graphics CenterX="940.0" CenterY="2805.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="APOD" GraphId="c79b8" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2115.5" CenterY="1657.0" Width="53.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P05090" /> </DataNode> <DataNode TextLabel="ABCA1 " GraphId="c7a4d" Type="Protein" GroupRef="a8260"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-9619752" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="2705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95477" /> </DataNode> <DataNode TextLabel="APOC2" GraphId="c7b19" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2111.5" CenterY="1437.0" Width="51.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P02655" /> </DataNode> <DataNode TextLabel="MYLIP gene" GraphId="c7b53" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1509.5" CenterY="1622.5" 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GraphId="c7ff2" Type="Metabolite" GroupRef="ec392"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028534" /> <Attribute Key="copies_num" Value="37" /> <Graphics CenterX="940.0" CenterY="3405.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="c87e8" Type="Protein" GroupRef="ecbc7"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028535" /> <Attribute Key="copies_num" Value="20" /> <Graphics CenterX="1080.0" CenterY="2705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="NR1H2 " GraphId="c88d1" Type="Protein" GroupRef="da1d6"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024381" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="2645.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55055" /> </DataNode> <DataNode TextLabel="miR-26B RISC " GraphId="c8d45" GroupRef="e9800"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9011867" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3185.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-9011856" /> </DataNode> <DataNode TextLabel="ABCA1gene:NR1H2,3:RXR:NR1H2,3 ligands" GraphId="c8e1b" Type="Complex"> <BiopaxRef>eaa</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="994.5" CenterY="398.0" Width="127.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9024330" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="c8f57" Type="Protein" GroupRef="fbd4e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024378" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="100.0" CenterY="3105.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="c8f85" Type="Protein" GroupRef="b6152"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035153" /> <Attribute Key="copies_num" Value="31" /> <Graphics CenterX="800.0" CenterY="3325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="c9080" Type="Protein" GroupRef="c8d93"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9624347" /> <Attribute Key="copies_num" Value="28" /> <Graphics CenterX="1780.0" CenterY="2665.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="ABCG8 gene " GraphId="c9143" Type="Protein" GroupRef="e54ea"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029595" /> <Attribute Key="copies_num" Value="21" /> <Graphics CenterX="660.0" CenterY="2905.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000143921" /> </DataNode> <DataNode TextLabel="EIF2C4 " GraphId="c91b0" Type="Protein" GroupRef="dd083"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9038554" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="1500.0" CenterY="3065.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HCK5" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="c9820" Type="Metabolite" GroupRef="f5992"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9618399" /> <Attribute Key="copies_num" Value="51" /> <Graphics CenterX="1640.0" CenterY="2945.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="UGT1A3&#xA;gene:NR1H2,3:RXR:NR1H2,3 ligand:NCOR" GraphId="c9987" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="447.5" CenterY="2497.0" Width="129.0" Height="64.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9029556" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="c9a47" Type="Metabolite" GroupRef="c8a5b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623370" /> <Attribute Key="copies_num" Value="53" /> <Graphics CenterX="1640.0" CenterY="3385.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="27-hydroxycholesterol " GraphId="caa7b" Type="Metabolite" GroupRef="f0c7f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028527" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="2805.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:76591" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="cb40d" Type="Protein" GroupRef="f828c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9031524" /> <Attribute Key="copies_num" Value="13" /> <Graphics CenterX="660.0" CenterY="3305.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="ARL4C" GraphId="cb55b" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1950.5" CenterY="1825.0" Width="49.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P56559" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="cba72" Type="Protein" GroupRef="f828c"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9031524" /> <Attribute Key="copies_num" Value="25" /> <Graphics CenterX="660.0" CenterY="3325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="CETP gene " GraphId="cbacd" Type="Protein" GroupRef="d0c4b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035197" /> <Attribute Key="copies_num" Value="23" /> <Graphics CenterX="660.0" CenterY="3205.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000087237" /> </DataNode> <DataNode TextLabel="NR1H2 " GraphId="cbace" Type="Protein" GroupRef="fca82"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="24" /> <Graphics CenterX="1360.0" CenterY="2765.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55055" /> </DataNode> <DataNode TextLabel="APOE gene" GraphId="cc028" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1492.5" CenterY="1268.5" Width="73.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000130203" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="cc594" Type="Protein" GroupRef="c8d93"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9624347" /> <Attribute Key="copies_num" Value="55" /> <Graphics CenterX="1780.0" CenterY="2725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="cc6ec" Type="Protein" GroupRef="b2228"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024349" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="240.0" CenterY="2705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="SCD gene " GraphId="cc88c" Type="Protein" GroupRef="ecbc7"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9028535" /> <Attribute Key="copies_num" Value="39" /> <Graphics CenterX="1080.0" CenterY="2925.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000099194" /> </DataNode> <DataNode TextLabel="TNRC6B " GraphId="ccdf5" Type="Protein" GroupRef="dd083"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9038554" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1500.0" CenterY="2925.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UPQ9" /> </DataNode> <DataNode TextLabel="UGT1A3&#xA;gene:NR1H2,3:RXR:NCOR" GraphId="ccec8" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="198.5" CenterY="2494.0" Width="127.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9029554" /> </DataNode> <DataNode TextLabel="TNRC6C " GraphId="cd5fd" Type="Protein" GroupRef="da881"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9038541" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="1500.0" CenterY="2705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HCJ0" /> </DataNode> <DataNode TextLabel="ARL4C gene" GraphId="cd66a" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1529.5" CenterY="1863.5" Width="81.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000188042" /> </DataNode> <DataNode TextLabel="APOC4 gene" GraphId="ce3d0" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1515.5" CenterY="1550.5" Width="83.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000267467" /> </DataNode> <DataNode TextLabel="KDM1B " GraphId="ceab8" Type="Protein" GroupRef="fbd4e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024378" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="100.0" CenterY="3365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8NB78" /> </DataNode> <DataNode TextLabel="NR1H3 mRNA" GraphId="cead6" Type="Rna"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1766.0" CenterY="1141.0" Width="122.0" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="990099" /> <Xref Database="Ensembl" ID="ENST00000441012" /> </DataNode> <DataNode TextLabel="22R-hydroxycholesterol " GraphId="ceb59" Type="Metabolite" GroupRef="ee612"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029543" /> <Attribute Key="copies_num" Value="19" /> <Graphics CenterX="520.0" CenterY="3165.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:67237" /> </DataNode> <DataNode TextLabel="NR1H3 " GraphId="ceb9a" Type="Protein" GroupRef="e5ea2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9658360" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2200.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="FABP6 gene" GraphId="cf00f" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1553.0" CenterY="2382.5" Width="80.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170231" /> </DataNode> <DataNode TextLabel="MYLIP 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<Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024381" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="100.0" CenterY="2685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13133" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="e1cb3" Type="Protein" GroupRef="ba53e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024330" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="380.0" CenterY="2865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="27-hydroxycholesterol " GraphId="e1dd6" Type="Metabolite" GroupRef="fca82"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035263" /> <Attribute Key="copies_num" Value="47" /> <Graphics 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<Xref Database="Reactome" ID="R-HSA-9011856" /> </DataNode> <DataNode TextLabel="GPS2 " GraphId="f1a36" Type="Protein" GroupRef="fbd4e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9024378" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="100.0" CenterY="3325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13227" /> </DataNode> <DataNode TextLabel="24(S)-hydroxycholesterol " GraphId="f1b2c" Type="Metabolite" GroupRef="e0019"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029599" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="380.0" CenterY="3345.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:34310" /> </DataNode> <DataNode TextLabel="24(S),25-epoxycholesterol " GraphId="f1bd3" Type="Metabolite" GroupRef="e54ea"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9029595" /> <Attribute Key="copies_num" Value="21" /> <Graphics CenterX="660.0" CenterY="2765.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:41633" /> </DataNode> <DataNode TextLabel="RXRB " GraphId="f1dce" Type="Protein" GroupRef="d1bd1"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9631294" /> <Attribute Key="copies_num" Value="30" /> <Graphics CenterX="1920.0" CenterY="2705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28702" /> </DataNode> <DataNode TextLabel="NR1H2,3:RXR:NR1H2,3&#xA;ligand:CETP gene" GraphId="f1e10" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1336.0" CenterY="871.0" Width="132.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9035197" /> </DataNode> <DataNode TextLabel="AGO2 " GraphId="f1f80" Type="Protein" GroupRef="dd083"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9038554" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="1500.0" CenterY="2985.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UKV8" /> </DataNode> <DataNode TextLabel="27-hydroxycholesterol " GraphId="f23f7" Type="Metabolite" GroupRef="e64e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9035268" /> <Attribute Key="copies_num" Value="49" /> <Graphics CenterX="1360.0" CenterY="3265.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:76591" /> </DataNode> <DataNode 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X="842.0" Y="2501.0" GraphRef="dd08d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029580" /> </Interaction> <Interaction GraphId="a0fb7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="619.0" Y="403.0" GraphRef="c3823" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024326" /> </Interaction> <Interaction GraphId="a1939"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1517.0" Y="2308.0" GraphRef="fdd3d" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="767.0" Y="2252.0" GraphRef="bc193" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608039" /> </Interaction> <Interaction GraphId="a1b1d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="662.0" Y="2389.0" GraphRef="e1c7e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657836" /> </Interaction> <Interaction GraphId="a2547"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1179.0" Y="869.0" GraphRef="aa453" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035133" /> </Interaction> <Interaction GraphId="a2737"> <Comment Source="Reactome">Liver X receptor LXRα (NR1H3) or LXRβ (NR1H2) heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF &amp; Gustafsson JA 1997). Under basal conditions, the NR1H2,3:RXR heterodimer is bound to a co-repressor complex in the promoter area of the target genes (Jakobsson T et al. 2009). On ligand activation the co-repressor complex dissociates and is replaced by coactivators. Chromatin immunoprecipitation (ChIP) assays showed the oxysterol-induced interaction of the nuclear receptor coactivator 1 (NCOA1, also known as SRC1) and E1A-associated protein p300 (EP300) with the DR-4 element of the ABCA1 gene promoter (Huuskonen J et al. 2004). This study was performed with human embryonic kidney 293T (HEK293) cells stably overexpressing FLAG-tagged LXRα (Huuskonen J et al. 2004). NCOA1 (SRC1) belongs to the family of p160 coactivators which interact directly with nuclear receptors via LXXLL motifs (L indicates leucine; X, any amino acid), and with other members of the p160 coactivator complex via AD1 and AD2 interaction domains (reviewed in: Xu J &amp; Li Q 2003; Xu L et al. 2009). NCOR1 recruits the transcriptional co-activator EP300 (Chan HM &amp; La Thangue NB 2001). NCOA1 and EP300 are thought to induce local changes in the nucleosome structure via co-activator binding activity, acetylation or methylation of histones and other components of the transcription unit (reviewed in Xu J &amp; Li Q 2003; Xu L et al. 2009; Chan HM &amp; La Thangue NB 2001). </Comment> <BiopaxRef>d23</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1097.0" Y="399.0" /> <Point X="1159.0" Y="399.0" /> <Anchor Position="0.0" Shape="None" GraphId="e5857" /> <Anchor Position="0.99" Shape="None" GraphId="d7645" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029551" /> </Interaction> <Interaction GraphId="a2e61"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1205.0" Y="959.0" GraphRef="acd9e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624353" /> </Interaction> <Interaction GraphId="a3245"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1428.0" Y="1114.0" GraphRef="f813d" RelX="0.9819819819819819" RelY="0.0" /> <Point X="1553.0" Y="1138.0" GraphRef="b4cd9" RelX="-60.5" RelY="-1.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035281" /> </Interaction> <Interaction GraphId="a34f1"> <Comment Source="Reactome">A small non-coding RNA miR-26 was identified as a liver X receptor (LXR or NR1H2,3)-responsive miRNA that is downregulated in the presence of LXR agonist T0901317 (Sun D et al. 2012). miR-26 suppressed the translation of ADP-ribosylation factor-like 4C (ARL4C or ARL7) mRNA in NR1H2,3 (LXR)â€�activated human (THP-1) and mouse (RAW264.7) macrophages. Bioinformatic tools for miRNA target prediction showed that the seed regions of miRâ€�26a and miRâ€�26b were complementary to the ARL4C 3′UTR (Sun D et al. 2012). The miR-26 binding sites in ARL4C 3′UTR were highly conserved among mammals (Sun D et al. 2012). Further, 3'UTR luciferase reporter assay using human embryonic kidney cells (HEK293T) showed that a miR-26 mimetic inhibits ARL4C 3′UTR luciferase reporter activity and this is absent with the mutant ARL4C 3′UTR firefly luciferase reporter (Sun D et al. 2012). Similar results were obtained for another NR1H2,3-regulated gene ATP-binding cassette transporter A1 (ABCA1). Moreover, miRâ€�26 was shown to suppress the NR1H2,3â€�dependent cholesterol efflux in RAW264.7 cells by targeting ARL4C and ABCA1 (Sun D et al. 2012). This Reactome event describes the miR-26-regulated translation of ARL4C mRNA in responce to NR1H2,3 ligands. The annotation is based on the study with GW3965 and T0901317, the synthetic agonists of NR1H2,3 (Sun D et al. 2012).</Comment> <BiopaxRef>c88</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1769.0" Y="1855.0" /> <Point X="1825.0" Y="1859.0" /> <Anchor Position="0.0" Shape="None" GraphId="e1e27" /> <Anchor Position="0.99" Shape="None" GraphId="af7b4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618392" /> </Interaction> <Interaction GraphId="a35e0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1046.0" Y="2248.0" GraphRef="b0a40" RelX="1.0" RelY="0.0" /> <Point X="1648.0" Y="2286.0" GraphRef="e5116" RelX="-7.5" RelY="-12.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608048" /> </Interaction> <Interaction GraphId="a3d8d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1179.0" Y="1883.0" GraphRef="d6138" RelX="0.9844961240310077" RelY="0.0" /> <Point X="1638.0" Y="1931.0" GraphRef="f5546" RelX="-15.0" RelY="-0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605063" /> </Interaction> <Interaction GraphId="a46c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1512.0" Y="2223.0" GraphRef="adfbb" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="845.0" Y="2174.0" GraphRef="bc8b3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="a4a27"> <Comment Source="Reactome">In addition to its well defined role as a transcription factor, liver X receptor β (LXRβ or NR1H2) can directly bind to the C-terminal region of ATP-binding cassette A1 (ABCA1) in the human macrophage-like (THP-1) and human embryonic kidney 293 (HEK293) cell lines to impact ABCA1 protein function (Hozoji M et al. 2008; Hozoji-Inada M et al. 2011). In the absence of cholesterol accumulation in THP-1 cells, the ABCA1:NR1H2 complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur (Hozoji M et al. 2008; Hozoji-Inada M et al. 2011). Exogenously added NR1H2 ligands, which mimic cholesterol accumulation, cause NR1H2 (LXRβ) to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux (Hozoji M et al. 2008; Hozoji-Inada M et al. 2011). Photoaffinity labeling experiments with 8-azido-[α-(32)P]ATP suggested that the interaction of NR1H2 (LXRβ) with ABCA1 inhibits ATP binding by ABCA1 (Hozoji-Inada M et al. 2011).</Comment> <BiopaxRef>dcb</BiopaxRef> <BiopaxRef>ec8</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2032.0" Y="490.0" /> <Point X="2035.0" Y="538.0" /> <Anchor Position="0.0" Shape="None" GraphId="b2154" /> <Anchor Position="0.99" Shape="None" GraphId="f0df7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9619756" /> </Interaction> <Interaction GraphId="a4f26"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="1063.0" Y="1707.0" GraphRef="c4a56" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035167" /> </Interaction> <Interaction GraphId="a507f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1818.0" Y="2113.0" GraphRef="e5093" RelX="2.3099999999999454" RelY="-0.010000000000218279" /> <Point X="1821.0" Y="2113.0" GraphRef="a95f2" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605056" /> </Interaction> <Interaction GraphId="a5154"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="924.0" Y="1970.0" GraphRef="db076" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="a51de"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="550.0" Y="2049.0" GraphRef="e102d" RelX="0.9534883720930233" RelY="0.0" /> <Point X="866.0" Y="2083.0" GraphRef="e211d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028525" /> </Interaction> <Interaction GraphId="a54da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="1088.0" Y="1627.0" GraphRef="de0c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657786" /> </Interaction> <Interaction GraphId="a5bef"> <Comment Source="Reactome">The stearoyl CoA desaturase (SCD) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SCD is an endoplasmic reticulum (ER) enzyme that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids that are either synthesized de novo or derived from the diet (Bene H et al. 2001; Paton CM &amp; Ntambi JM 2009). Liver X receptors (LXRα/NR1H3 or LXRβ/NR1H2) are oxysterol receptors that regulate the gene expression of SCD. The evidence for the Reactome event of the induction of SCD gene expression by NR1H3 or NR1H2 comes from the studies with T0901317, the synthetic NR1H2,3 agonist, that has been shown to increase SCD gene expression in mouse liver and human arterial endothelial cells (HAEC) by 10- and 3-fold, respectively (Chu K et al. 2006; Peter A et al. 2008). Treatment with 22(R)-hydroxycholesterol, a natural ligand of NR1H2,3, increased the SCD activity in mouse macrophages J774 and thus supported the ability of NR1H2,3 to regulate SCD (Wang Y et al. 2004). NR1H2,3 has been presumed to regulate SCD protein level through the activation of sterol regulatory element-binding protein (SREBP1) and its consequent binding to SREBP1 binding site (SRE) (Schultz JR et al. 2000; Zhang X et al. 2014). However, studies with SREBP1c -/- mice have suggested that NR1H2,3 upregulate SCD in an SREBP1c-independent manner (Chu K et al. 2006). In HAEC cells, the NR1H2,3 activation increased SCD mRNA and protein expression, which served to protect the cells from saturated fatty acid-induced lipotoxicity, apoptosis and IL-6 and IL-8 expression (Peter A et al. 2008). Analysis of hepatic lipogenic gene expression indicated that nuclear receptor-interacting protein 140 (RIP140 or NRIP1) was required for the ability of NR1H3 to stimulate the expression of the SCD gene in WT and NRIP1 null mice after administration of T0901317 (Herzog B et al. 2007). These findings are supported by the failure of T0901317 to stimulate the expression of SCD gene in cultured human hepatoma HuH7 cells depleted of NRIP1 by siNRIP1 (Herzog B et al. 2007). 2007). Studies performed with T0901317 in wildtype vs. NR1H3-/- (LXRα-/-) and NR1H2 (LXRβ -/-) mice suggest that SCD1 is primarily regulated by NR1H3 (Zhang X et al. 2014).</Comment> <BiopaxRef>b38</BiopaxRef> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1571.0" Y="2013.0" /> <Point X="1821.0" Y="2014.0" /> <Anchor Position="0.0" Shape="None" GraphId="d3f7f" /> <Anchor Position="0.99" Shape="None" GraphId="f7403" /> <Anchor Position="0.5" Shape="None" GraphId="c410e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605060" /> </Interaction> <Interaction GraphId="a5c0e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1302.0" Y="1310.0" GraphRef="d7f65" RelX="0.7999999999999545" RelY="0.0" /> <Point X="1305.0" Y="1310.0" GraphRef="a7290" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031518" /> </Interaction> <Interaction GraphId="a6486"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2015.0" Y="702.0" GraphRef="f8df7" RelX="4.400000000000091" RelY="0.009999999999990905" /> <Point X="2018.0" Y="703.0" GraphRef="fcd13" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029531" /> </Interaction> <Interaction GraphId="a803d"> <Comment Source="Reactome">Cholesterol-loading or treatment with the synthetic agonists of liver X-receptors alpha (LXRα, NR1H3) and beta (LXRβ, NR1H2), such as T0901317 or GW3965, signiï¬�cantly induced the expression of ADP-ribosylation factor-like 4C (ARL4C or ARL7) in murine RAW 264.7 and human THP1 macrophage cell lines (Hong C et al. 2011; Engel T et al. 2004; Sun D et al. 2012). Similar regulation of ARL4C mRNA expression was observed in human peripheral blood-derived monocytes (Hong C et al. 2011). Sequence analysis of the ARL4C 5'-flanking region identified two LXR response elements (LXRE) containing variant direct repeats with a 4 nucleotide spacer (DR4) at –1405 bp and −5215 bp relative to the transcription start site (Hong C et al. 2011). Electrophoretic mobility shift assay showed that LXR:RXR heterodimers efficiently bind the putative ARL4C LXREs to regulate transcription from the promoter (Hong C et al. 2011).</Comment> <BiopaxRef>d13</BiopaxRef> <BiopaxRef>c6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1040.0" Y="1809.0" /> <Point X="1213.0" Y="1806.0" /> <Anchor Position="0.0" Shape="None" GraphId="a568f" /> <Anchor Position="0.99" Shape="None" GraphId="fa490" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618407" /> </Interaction> <Interaction GraphId="a876e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1259.0" Y="1113.0" GraphRef="cdec9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035185" /> </Interaction> <Interaction GraphId="a8b2a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2083.0" Y="1437.0" GraphRef="d60be" RelX="5.289999999999964" RelY="-0.06999999999993634" /> <Point X="2086.0" Y="1437.0" GraphRef="c7b19" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031527" /> </Interaction> <Interaction GraphId="a8ba1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1495.0" Y="2137.0" GraphRef="bfa08" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="866.0" Y="2083.0" GraphRef="e211d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028525" /> </Interaction> <Interaction GraphId="a9454"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1766.0" Y="1122.0" GraphRef="cead6" RelX="0.0" RelY="-1.0" /> <Point X="1764.0" Y="1127.0" GraphRef="cdf10" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605052" /> </Interaction> <Interaction GraphId="a94f2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1828.0" Y="1868.0" GraphRef="a2d7e" RelX="-1.0" RelY="0.0" /> <Point X="1864.0" Y="1823.0" GraphRef="f1340" RelX="-19.0" RelY="-0.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618405" /> </Interaction> <Interaction GraphId="a9650"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2024.0" Y="805.0" GraphRef="b25f5" RelX="4.460000000000036" RelY="-0.009999999999990905" /> <Point X="2027.0" Y="806.0" GraphRef="e7cb1" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029591" /> </Interaction> <Interaction GraphId="a9ddd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1087.0" Y="349.0" GraphRef="e73d5" RelX="0.9622641509433962" RelY="0.0" /> <Point X="1097.0" Y="399.0" GraphRef="e5857" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029551" /> </Interaction> <Interaction GraphId="aa009"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1750.0" Y="423.0" GraphRef="f609b" RelX="-0.010101010101010102" RelY="-1.0" /> <Point X="1816.0" Y="272.0" GraphRef="a8812" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657791" /> </Interaction> <Interaction GraphId="aa05e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1269.0" Y="960.0" GraphRef="ae736" RelX="0.6400000000001" RelY="0.009999999999990905" /> <Point X="1272.0" Y="962.0" GraphRef="d19cc" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624353" /> </Interaction> <Interaction GraphId="aa506"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="511.0" Y="2497.0" GraphRef="c9987" RelX="0.9844961240310077" RelY="0.0" /> <Point X="515.0" Y="2496.0" GraphRef="edef1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029566" /> </Interaction> <Interaction GraphId="aac9d"> <Comment Source="Reactome">Fatty acid synthase (FAS or FASN) is a central enzyme in de novo lipogenesis and an established target of the sterol regulatory element-binding transcription factor 1 (SREBP1 or SREBF1) pathway. FASN is also induced by agonists of liver X receptor α (LXRα) and LXRβ (also known as NR1H3 and NR1H2, respectively) in various mammalian cells including human monocyte-like THP-1 and hepatocellular carcinoma HepG2 cell lines (Joseph SB et al. 2002; Matsukuma KE et al. 2007). Transient transfection assays showed that sequences located between −700 and −150 bp as well as between −135 and +67 in the FASN promoter mediated the response to NR1H3 and NR1H2 and their synthetic ligands when HepG2 cells were transfected with luciferase reporter constructs containing the rat FAS promoter or a series of 5' deletions in the rat FAS promoter along with expression vectors for NR1H3 and RXRα or NR1H2 and RXRα (Joseph SB et al. 2002). Further, the vast majority of the NR1H2, NR1H3 response was conferred by the sequence between −700 and −150 bp when Hep2G cells were cultured in the presence of high levels of cholesterol or 25-hydroxycholesterol (25-HC), conditions known to suppress SREBP cleavage thus reducing the concentration of nuclear SREBPs to undetectable levels (Joseph SB et al. 2002). A sequence analysis showed that in addition to tandem SREBP sites between −71 and +54, the FASN promoter contains a high affinity LXR response element (LXRE) containing a variant direct-repeat-4 (DR4) motif (between −669 and −655 bp in the rat promoter) that is conserved in diverse animal species including chicken, rat, and humans (Joseph SB et al. 2002). The LXRE and SREBP binding sites independently conferred NR1H3 responsiveness on the FAS promoter, and maximal induction required both SREBP and NR1H3 transcription factors. Gel mobility shift analysis using in vitro translated NR1H3 and RXRα proteins and radiolabeled oligonucleotides confirmed that FASN LXRE binds NR1H3:RXR heterodimers (Joseph SB et al. 2002). These results suggest that NR1H3 regulate FASN expression through direct interaction with an upstream LXRE sequence in the region of FASN promoter as well as indirectly by inducing SREBP1c expression involving sequences between −135 and +67 bp (Joseph SB et al. 2002). Nuclear receptor-interacting protein 1 (NRIP1, also known as receptor-interacting protein 140 (RIP140)) was found to bind directly to the FAS gene promoter in the vicinity of the LXRE and functioned as a positive cofactor for the NR1H2 or NR1H3 - regulated expression of FASN gene in human liver HuH7 cells (Herzog B et al. 2007). </Comment> <BiopaxRef>fad</BiopaxRef> <BiopaxRef>fab</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="963.0" Y="1881.0" /> <Point X="1048.0" Y="1882.0" /> <Anchor Position="0.0" Shape="None" GraphId="ab3d7" /> <Anchor Position="0.99" Shape="None" GraphId="b36ad" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="aad50"> <Comment Source="Reactome">UDP Glucuronosyltransferase Family 1 Member A3 (UGT1A3) is an enzyme that catalyzes the C24-glucuronidation of the primary bile acid (chenodeoxycholic acid, CDCA) and secondary bile acid (lithocholic acid, LCA). In human hepatoma HepG2 cells, an NR1H2,3 (liver X receptor, LXR) agonist T0901317 induced UGT1A3 expression in a dose- and time-dependent manner (Verreault M et al. 2006). Endogenous NR1H2,3 (LXR) agonists were also investigated by measuring UGT1A3 expression in HepG2 cells treated with 22R-hydroxycholesterol or 24S-hydroxycholesterol. Although the strongest increase in UGT1A3 mRNA levels was reached in the presence of T0901317, 24S-hydroxycholesterol treatment produced a significant induction of UGT1A3 expression, whereas 22R-hydroxycholesterol displayed no significant effects. Furthermore, UGT1A3 gene induction occured through binding of the LXRalpha:RXRalpha heterodimer to a functional LXR response element (LXRE) which was identified in the proximal part of the UGT1A3 promoter gene by site-directed mutagenesis, electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (Verreault M et al. 2006).</Comment> <BiopaxRef>b21</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="304.0" Y="2496.0" /> <Point X="380.0" Y="2497.0" /> <Anchor Position="0.0" Shape="None" GraphId="aab9a" /> <Anchor Position="0.99" Shape="None" GraphId="e4531" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029517" /> </Interaction> <Interaction GraphId="ac0b8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="964.0" Y="2080.0" GraphRef="ab8b6" RelX="0.9800000000000182" RelY="-0.03000000000020009" /> <Point X="967.0" Y="2079.0" GraphRef="d7f48" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028525" /> </Interaction> <Interaction GraphId="ac407"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="924.0" Y="1970.0" GraphRef="db076" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="ad224"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="698.0" Y="402.0" GraphRef="d835e" RelX="0.7899999999999636" RelY="-0.009999999999990905" /> <Point X="701.0" Y="402.0" GraphRef="ae611" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024326" /> </Interaction> <Interaction GraphId="ad689"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="293.0" Y="799.0" GraphRef="d3573" RelX="-0.009900990099009901" RelY="1.0" /> <Point X="767.0" Y="2252.0" GraphRef="bc193" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608039" /> </Interaction> <Interaction GraphId="ada21"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1489.0" Y="1863.0" GraphRef="cd66a" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1040.0" Y="1809.0" GraphRef="a568f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618407" /> </Interaction> <Interaction GraphId="ade35"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1577.0" Y="2137.0" GraphRef="bfa08" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="1587.0" Y="2114.0" GraphRef="c88e1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605056" /> </Interaction> <Interaction GraphId="adeaf"> <Comment Source="Reactome">In transient transfection assays performed in human hepatoma HepG2 cells, NR1H3 (LXR alpha) was found to interact with the NCOA1 (SRC1) and NCOR cofactors to regulate the UGT1A3 gene promoter (Verreault M et al. 2006). Unliganded LXR:RXR actively suppresses transcription by recruiting the co-repressor NCOR complex. Agonist binding induces dissociation of the co-repressor, which results in moderate stimulation of transcription and later recruits co-activators such as NCOA1 leading to maximal stimulation of transcription.</Comment> <BiopaxRef>b21</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="842.0" Y="2501.0" /> <Point X="1042.0" Y="2503.0" /> <Anchor Position="0.0" Shape="None" GraphId="dd08d" /> <Anchor Position="0.99" Shape="None" GraphId="e240e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029580" /> </Interaction> <Interaction GraphId="ae4cf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2086.0" Y="1657.0" GraphRef="f2d9d" RelX="5.0" RelY="-0.03999999999996362" /> <Point X="2089.0" Y="1657.0" GraphRef="c79b8" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657767" /> </Interaction> <Interaction GraphId="ae6ee"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1712.0" Y="2386.0" GraphRef="dadae" RelX="1.099999999999909" RelY="0.2699999999999818" /> <Point X="1715.0" Y="2395.0" GraphRef="dadab" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9607342" /> </Interaction> <Interaction GraphId="af731"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1474.0" Y="1550.0" GraphRef="ce3d0" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1171.0" Y="1489.0" GraphRef="c129d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035143" /> </Interaction> <Interaction GraphId="afd20"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1794.0" Y="248.0" GraphRef="de6a1" RelX="1.0" RelY="0.0" /> <Point X="1816.0" Y="272.0" GraphRef="a8812" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657791" /> </Interaction> <Interaction GraphId="b030f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1267.0" Y="869.0" GraphRef="e0cdf" RelX="0.8800000000001091" RelY="0.0" /> <Point X="1270.0" Y="871.0" GraphRef="f1e10" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035133" /> </Interaction> <Interaction GraphId="b0329"> <Comment Source="Reactome">The ADP-ribosylation factor-like protein 4C (ARL4C, also known as ARL7) gene is transcribed to yield mRNA. Cholesterol-loading or treatment with the synthetic agonists of liver X-receptors alpha (LXRα, NR1H3) and beta (LXRβ, NR1H2), such as T0901317 or GW3965, signiï¬�cantly induced the expression of ARL4C in murine RAW 264.7 and human THP1 macrophage cell lines (Hong C et al. 2011; Engel T et al. 2004; Sun D et al. 2012). Transcriptional studies of primary macrophages from single and double knockout NR1H2 or NR1H3 mice treated with LXR ligands GW3965 or T0901317 revealed that both receptors independently regulate ARL4C and induction was abolished only in the absence of both receptors (Hong C et al. 2011). Induction of ARL4C mRNA expression by NR1H2 or NR1H3 agonist was preserved in the presence of cycloheximide, indicating that new protein synthesis is not required for the effect of LXRs on ARL7. Similar regulation of ARL4C mRNA expression was observed in human peripheral blood-derived monocytes (Hong C et al. 2011). NR1H2 or NR1H3 stimulation of ARL4C has been shown to transport cholesterol to the membrane for the ATP-binding cassette transporter A1 (ABCA1)-associated cholesterol removal (Engel T et al. 2004). Overexpression of ARL4C in HeLa cells enhances APOA1-mediated cholesterol efflux (Engel T et al. 2004).</Comment> <BiopaxRef>c6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1579.0" Y="1840.0" /> <Point X="1716.0" Y="1832.0" /> <Anchor Position="0.0" Shape="None" GraphId="b53ec" /> <Anchor Position="0.99" Shape="None" GraphId="e9429" /> <Anchor Position="0.5" Shape="None" GraphId="b59d0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618394" /> </Interaction> <Interaction GraphId="b0c56"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="550.0" Y="2049.0" GraphRef="e102d" RelX="0.9534883720930233" RelY="0.0" /> <Point X="845.0" Y="2174.0" GraphRef="bc8b3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="b0c8c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1827.0" Y="1141.0" GraphRef="cead6" RelX="1.0" RelY="0.0" /> <Point X="1841.0" Y="1164.0" GraphRef="ba4ec" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9038545" /> </Interaction> <Interaction GraphId="b10d3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1040.0" Y="1809.0" GraphRef="a568f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618407" /> </Interaction> <Interaction GraphId="b1cca"> <Comment Source="Reactome">Apolipoprotein D (APOD) is an atypical apolipoprotein that belongs to the lipocalin family, and is expressed by a wide variety of cells and tissues (Drayna D et al. 1986). The liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) were found to regulate the expression of the APOD gene in cultured cells and in vivo (Hummasti S et al. 2004; Lai C-J et al. 2017). Synthetic LXR agonist treatment of mouse adipocytes (3T3-L1 cells) and human umbilical vein endothelial cells (HUVECs) resulted in increased mRNA and protein levels of APOD (Hummasti S et al. 2004; Lai C-J et al. 2017). An LXR response element (LXRE) was identified in the human APOD gene promoter, and binding of LXRα (NR1H3):RXRa heterodimers was demonstrated by electrophoretic mobility shift assay (EMSA) and luciferase cell reporter assay (Hummasti S et al. 2004). Mice treated with synthetic LXR agonists exhibited increased APOD mRNA levels in adipose tissue, skeletal muscle and cerebellum, but not liver (Hummasti S et al. 2004; Repa JJ et al. 2007). In humans, APOD is found in the plamsa, associated with high-density lipoprotein (HDL), and polymorphisms have been linked to metabolic disease. APOD has also been suggested to be neuroprotective (Pascua-Maestro R et al 2019).</Comment> <BiopaxRef>d10</BiopaxRef> <BiopaxRef>b5e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1088.0" Y="1627.0" /> <Point X="1267.0" Y="1629.0" /> <Anchor Position="0.0" Shape="None" GraphId="de0c1" /> <Anchor Position="0.99" Shape="None" GraphId="b0282" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657786" /> </Interaction> <Interaction GraphId="b261c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="550.0" Y="2049.0" GraphRef="e102d" RelX="0.9534883720930233" RelY="0.0" /> <Point X="924.0" Y="1970.0" GraphRef="db076" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="b2bcc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1088.0" Y="1627.0" GraphRef="de0c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657786" /> </Interaction> <Interaction GraphId="b42e8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1593.0" Y="2382.0" GraphRef="cf00f" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1602.0" Y="2359.0" GraphRef="cb097" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9607342" /> </Interaction> <Interaction GraphId="b462f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1420.0" Y="1211.0" GraphRef="eed7e" RelX="1.0" RelY="0.0" /> <Point X="1592.0" Y="1247.0" GraphRef="dd058" RelX="-227.5" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031512" /> </Interaction> <Interaction GraphId="b463f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1285.0" Y="1209.0" GraphRef="a6aad" RelX="0.31999999999993634" RelY="-0.009999999999990905" /> <Point X="1288.0" Y="1211.0" GraphRef="eed7e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031522" /> </Interaction> <Interaction GraphId="b467c"> <Comment Source="Reactome">Liver X receptor alpha (LXRα or NR1H3) is regarded as the major regulator of the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 mRNA expression. The synthetic agonist T0901317 of NR1H2, 3 markedly upregulated ABCG5 and ABCG8 expression in the small intestine and liver of wild type, but not NR1H3-knockout mice (Repa JJ et al. 2002; van der Veen et al. 2007). The human ABCG5 and ABCG8 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species. Using a reporter construct, the intergenic region was found to act as a bidirectional promoter and to harbor binding sites for hepatocyte nuclear factor 4α (HNF4α), liver receptor homolog 1 (LRH1) and GATA transcription factors (Remaley AT et al. 2002; Sumi K et al. 2007; Freeman LA et al. 2004). Through elaborate deletion studies, two regions containing putative LXR responsive elements (LXRE) were identified in ABCG5 and ABCG8 genes (Back SS et al. 2013). Electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP) and cell reporter assays demonstrated the binding of NR1H3 (and RXR) to two intronic regions of the human ABCG8 gene to confer LXR-mediated regulation of ABCG5 and ABCG8 genes in human liver carcinoma HepG2 cells (Back SS et al. 2013).&lt;p&gt;In mammalian cells, ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for developing premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001).</Comment> <BiopaxRef>c9e</BiopaxRef> <BiopaxRef>db4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1177.0" Y="767.0" /> <Point X="1264.0" Y="766.0" /> <Anchor Position="0.0" Shape="None" GraphId="ca8b0" /> <Anchor Position="0.99" Shape="None" GraphId="cb517" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029555" /> </Interaction> <Interaction GraphId="b48f9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1214.0" Y="1403.0" GraphRef="cf535" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031521" /> </Interaction> <Interaction GraphId="b52b5"> <Comment Source="Reactome">The UGT1A3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.</Comment> <BiopaxRef>b21</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1610.0" Y="2497.0" /> <Point X="1905.0" Y="2229.0" /> <Anchor Position="0.0" Shape="None" GraphId="e91c4" /> <Anchor Position="0.99" Shape="None" GraphId="c8e0f" /> <Anchor Position="0.5" Shape="None" GraphId="b0c61" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029536" /> </Interaction> <Interaction GraphId="b613f"> <Comment Source="Reactome">ATP Binding Cassette Subfamily G Member 1 (ABCG1, formerly called “whiteâ€� and/or ABCG8) expression is induced upon activation of liver X receptors (LXRα/NR1H3 or LXRβ/NR1H2) (Sabol SL et al. 2005; Beyea MM et al. 2007). The ABCG1 gene has been mapped to chromosome 21q22.3 and multiple human ABCG1 transcripts have been detected resulting from different transcription initiation sites and alternative mRNA splicing (Croop JM et al 1997; Langmann T et al. 2000; Lorkowski S et al. 2001; Kennedy MA et al. 2001). Induction of ABCG1 expression by NR1H2,3 agonists likely involves the presence of multiple LXR response elements (LXRE) through the promoter region of the ABCG1 gene (Kennedy MA et al. 2001; Sabol SL et al. 2005; Uehara Y et al. 2007). Studies in ABCG1 knockout mice revealed that ABCG1 is primarily expressed in macrophages, endothelial cells, and lymphocytes. However, it is also found in Kupffer cells and hepatocytes (Kennedy MA et al. 2005). ABCG1 exhibits a tissue specific expression pattern with high expression levels of ABCG1 found in lung, brain, spleen, adrenal glands, heart and liver (Croop JM et al 1997; Klucken J et al. 2000). ABCG1 plays an important role in cholesterol efflux (Kennedy MA et al. 2005; Wang N et al. 2004). In contrast to ABCA1, which transports cholesterol to lipid-poor apolipoprotein acceptors, ABCG1 transports cholesterol to preformed high-density lipoprotein (HDL) particles. A synergistic relationship between ABCA1 and ABCG1 has been proposed, whereby ABCA1 promotes lipidation of lipid-poor apoproteins and thus generating HDL-like acceptors for ABCG1-mediated cholesterol efflux (Gelissen IC et al. 2006). Beyond a role in cellular lipid homeostasis, ABCG1 participates in glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase (Sturek JM et al. 2010; Olivier M et al. 2012; Hardy LM et al. 2017).&lt;p&gt;G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2, NR1H3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009).</Comment> <BiopaxRef>eaa</BiopaxRef> <BiopaxRef>a54</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1588.0" Y="593.0" /> <Point X="2021.0" Y="594.0" /> <Anchor Position="0.0" Shape="None" GraphId="a6170" /> <Anchor Position="0.99" Shape="None" GraphId="a96fa" /> <Anchor Position="0.5" Shape="None" GraphId="b631f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024361" /> </Interaction> <Interaction GraphId="b658a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1213.0" Y="1806.0" GraphRef="fa490" RelX="1.7300000000000182" RelY="-0.029999999999972715" /> <Point X="1216.0" Y="1805.0" GraphRef="f2416" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618407" /> </Interaction> <Interaction GraphId="b6b01"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="365.0" GraphRef="b70f2" RelX="-1.0" RelY="0.0" /> <Point X="1901.0" Y="442.0" GraphRef="a644b" RelX="-9.5" RelY="0.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618479" /> </Interaction> <Interaction GraphId="b7209"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1528.0" Y="1268.0" GraphRef="cc028" RelX="0.9726027397260274" RelY="-0.0196078431372549" /> <Point X="1538.0" Y="1245.0" GraphRef="f6a37" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031512" /> </Interaction> <Interaction GraphId="b757d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1513.0" Y="2382.0" GraphRef="cf00f" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="720.0" Y="2323.0" GraphRef="ffb0b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9631296" /> </Interaction> <Interaction GraphId="b75a9"> <Comment Source="Reactome">The oxysterol receptors liver X receptor alpha (LXRα, NR1H3) and LXRβ (NR1H2) were reported to mediate hepatic lipogenesis in rodents and humans by direct binding and upregulation of the sterol regulatory element-binding protein 1c (SREBP1 or SREBF1), which controls the transcription of genes involved in fatty acid (FA) biosynthesis (Schultz JR et al. 2000; Repa JJ et al. 2000; Yoshikawa T et al. 2001). The SREBF1 gene can produce two proteins, SREBP1a and SREBP1c, by use of different promoters (Hua X et al. 1995) and unique first exons (Shimomura I et al. 1997). In humans and mice, the SREBP1c is the predominant SREBF1 isoform in the liver that regulates FA metabolism (Sato R 2010; Horton JD et al. 2002; Shimomura I et al. 1997). NR1H2 &amp; NR1H3 were shown to activate the mouse SREBF1 (SREBP1c) promoter (Repa JJ et al. 2000; Yoshikawa T et al. 2001). In cell transfection studies using human embryonic kidney 293 (HEK293) cells, expression of either NR1H2 or NR1H3 activated the SREBF1 promoter-luciferase reporter gene in a dose-dependent manner (Yoshikawa T et al. 2001). Deletion and mutation studies, as well as gel mobility shift assays, identified two LXREs in the SREBF1 promoter region that regulate expression of SREBP1c by both LXR and RXR agonists (Repa JJ et al. 2000; Yoshikawa T et al. 2001). In mice receiving oral cholesterol, T0901317 (LXR agonist) or LG268 (RXR agonist), SREBP1c mRNA levels are elevated in nearly all tissues tested (Repa JJ et al. 2000). Of note, insulin-mediated transcriptional upregulation of SREBP-1c also maps to the prominent LXRE in this gene promoter, and appears to require LXRs (Chen G. et al. 2004), as well as C/EBPβ (Tian JY et al. 2016) and BHLHE40 (Tian J et al. 2018). In human hepatoma HepG2 cells, SREBF1 mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR:RXR activation can induce endogenous SREBF1 expression (Yoshikawa T et al. 2001). In hepatocytes NRIP1 (RIP140) was reported to act as a coactivator of NR1H2 or NR1H3-induced lipogenesis (Herzog B et al. 2007).</Comment> <BiopaxRef>c17</BiopaxRef> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="866.0" Y="2083.0" /> <Point X="964.0" Y="2080.0" /> <Anchor Position="0.0" Shape="None" GraphId="e211d" /> <Anchor Position="0.99" Shape="None" GraphId="ab8b6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028525" /> </Interaction> <Interaction GraphId="b79fb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2021.0" Y="594.0" GraphRef="a96fa" RelX="4.329999999999927" RelY="0.009999999999990905" /> <Point X="2024.0" Y="595.0" GraphRef="f348f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024361" /> </Interaction> <Interaction GraphId="b7aed"> <Comment Source="Reactome">The Reactome event shows liver X receptor (LXR or NR1H2 or NR1H3)-mediated regulation of the perilipin 1 (PLIN1) gene by naturally occurring NR1H2,3 agonists, oxysterols. This event is based on the data reported for the synthetic agonist GW3965 (Stenson BM et al. 2011). Upon activation by GW3965, NR1H2 (or NR1H3) was found to bind to the proximal regions of the PLIN1 promoter to downregulate PLIN1 expression in differentiated human and murine adipocytes. By selective knockdown of either NR1H2 or NR1H3 using siRNA in human adipocytes, NR1H3 (LXRα) was shown to be the major isoform mediating the lipolysis-related effects of NR1H2,3 (Stenson BM et al. 2011).</Comment> <BiopaxRef>d9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="767.0" Y="2252.0" /> <Point X="931.0" Y="2249.0" /> <Anchor Position="0.0" Shape="None" GraphId="bc193" /> <Anchor Position="0.99" Shape="None" GraphId="a2394" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608039" /> </Interaction> <Interaction GraphId="b7d01"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="845.0" Y="2174.0" GraphRef="bc8b3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="b7e96"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1388.0" Y="1631.0" GraphRef="d5581" RelX="0.9831932773109243" RelY="0.0" /> <Point X="1624.0" Y="1661.0" GraphRef="a213d" RelX="-212.0" RelY="2.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657767" /> </Interaction> <Interaction GraphId="b831a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1182.0" Y="518.0" GraphRef="c031c" RelX="1.0" RelY="0.0" /> <Point X="1190.0" Y="551.0" GraphRef="bdca9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="b88db"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1348.0" Y="1805.0" GraphRef="f2416" RelX="1.0" RelY="0.0" /> <Point X="1647.0" Y="1842.0" GraphRef="b59d0" RelX="-0.5" RelY="6.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618394" /> </Interaction> <Interaction GraphId="b89a7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1284.0" Y="401.0" GraphRef="de15a" RelX="1.0" RelY="0.0" /> <Point X="1320.0" Y="396.0" GraphRef="eed89" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029561" /> </Interaction> <Interaction GraphId="b8ccf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1115.0" Y="1564.0" GraphRef="caf5d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623366" /> </Interaction> <Interaction GraphId="b905c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1313.0" Y="355.0" GraphRef="ac977" RelX="0.9555555555555556" RelY="0.0" /> <Point X="1320.0" Y="396.0" GraphRef="eed89" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029561" /> </Interaction> <Interaction GraphId="b93d5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1177.0" Y="767.0" GraphRef="ca8b0" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029555" /> </Interaction> <Interaction GraphId="b95be"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1264.0" Y="766.0" GraphRef="cb517" RelX="0.8699999999998909" RelY="-0.009999999999990905" /> <Point X="1267.0" Y="767.0" GraphRef="cf185" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029555" /> </Interaction> <Interaction GraphId="b981c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2018.0" Y="442.0" GraphRef="eae23" RelX="2.150000000000091" RelY="0.0" /> <Point X="2021.0" Y="442.0" GraphRef="eefb2" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618479" /> </Interaction> <Interaction GraphId="b9cc6"> <Comment Source="Reactome">The CETP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CETP expression can be transcriptionally activated by liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) that belong to the nuclear receptor superfamily of ligand-activated transcription factors. Activation of NR1H2,3 induced expression via an LXR response element (LXRE) consisting of 2 hexanucleotide sequences separated by 4 intervening bases (an LXRE of the DR4 type) in the CETP promoter (Luo Y &amp;amp; Tall AR 2000), which may be more responsive to LXRα rather than LXRβ (Honzumi S et al. 2010). Treatment with T0901317, a synthetic agonist of NR1H2,3, increased CETP mRNA levels in human liver carcinoma HepG2 cells by approximately 220%, while NR1H3 silencing markedly diminished the increased expression of CETP (Shimada A et al. 2016). It should be noted that CETP is not expressed in the mouse or rat (it is a pseudogene in these species, Hogarth CA et al. 2003) so studies of LXR-mediated regulation of CETP have been performed in human, hamster, and non-human primates (Groot PHE, et al. 2005).</Comment> <BiopaxRef>a64</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1573.0" Y="903.0" /> <Point X="2082.0" Y="904.0" /> <Anchor Position="0.0" Shape="None" GraphId="c23a2" /> <Anchor Position="0.99" Shape="None" GraphId="cd741" /> <Anchor Position="0.5" Shape="None" GraphId="fde8b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035169" /> </Interaction> <Interaction GraphId="b9ef3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="866.0" Y="2083.0" GraphRef="e211d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028525" /> </Interaction> <Interaction GraphId="ba1df"> <Comment Source="Reactome">Natural and synthetic ligands of liver X receptors (LXRα, NR1H3 and LXRβ, NR1H2) induced expression of a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 in both human and mouse macrophages (Mak PA et al. 2002). The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXR α/β-/- mice (Mak PA et al. 2002). Cell reporter assays suggest that the LXR response elements (LXRE) in the multienhancer regions ME.1 and ME.2, which confer tissue-specific expression in macrophages and adipocytes (Shih SJ et al. 2000), are necessary for the expression of this gene cluster (Mak PA et al. 2002). These secreted apolipoproteins regulate lipid transport and catabolism. APOC2 is recognized as an activator of lipoprotein lipase (reviewed in Wolska A et al. 2017). Thus the genetic deficiency of APOC2 results in a phenotype that resembles lipoprotein lipase deficiency, and is aptly called hyperlipoproteinemia type IB. Individuals lacking APOC2 exhibit hyperchylomicronemia and hypertriglyceridemia (reviewed in Wolska A et al. 2017).</Comment> <BiopaxRef>db5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1214.0" Y="1403.0" /> <Point X="1275.0" Y="1403.0" /> <Anchor Position="0.0" Shape="None" GraphId="cf535" /> <Anchor Position="0.99" Shape="None" GraphId="bbfee" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031521" /> </Interaction> <Interaction GraphId="bae07"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="991.0" Y="1969.0" GraphRef="d5e29" RelX="0.6699999999999591" RelY="-0.009999999999990905" /> <Point X="994.0" Y="1970.0" GraphRef="e68db" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="bc70e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="720.0" Y="2323.0" GraphRef="ffb0b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9631296" /> </Interaction> <Interaction GraphId="bd7f8"> <Comment Source="Reactome">The ATP-binding cassette transporter A1 (ABCA1) gene is transcribed to yield mRNA.&lt;p&gt;T0901317 or GW3965, two synthetic agonists of liver X-receptors (LXRα, NR1H3 and LXRβ, NR1H2) or cholesterol-loading signiï¬�cantly induced the expression of ABCA1 mRNA in mouse RAW 264.7 and human THP1 macrophage cell lines (Costet P et al. 2000; Venkateswaran A et al. 2000; Whitney KD et al. 2001; Jakobsson T et al. 2009). Similar regulation of ABCA1 mRNA expression by NR1H2, 3 agonists was observed in human peripheral blood-derived monocytes (Larrede S et al. 2009). Treatment with T0901317 increased expression of ABCA1 mRNA in variety of cells and tissues isolated from wild type but not LXR-/- mice (lacking both NR1H3 and NR1H2) (Repa JJ et al. 2000; Wagner BL et al. 2003). At the same time, NR1H2, 3 repressed basal expression of ABCA1 in a tissue-specific manner, occurring in macrophages and intestinal mucosa but not in several other mouse tissues (Wagner BL et al. 2003). Treatment of human THP-1 macrophages with endogenous (25-hydroxycholesterol) or synthetic (T0901317) ligands of NR1H2,3 stimulated both transcriptional and posttranscriptional events to enhance ABCA1 expression (Ignatova ID et al. 2013). NR1H2,3-induced expression of ABCA1 is thought to promote ABCA1-mediated cellular cholesterol transport across the plasma membrane to lipid-poor apolipoproteins, such as ApoA1 and ApoE in the generation of nascent high-density lipoproteins (HDL) particles (Ignatova ID et al. 2013; Vedhachalam C et a. 2007). Loss of ABCA1 in humans results in Tangier disease, a condition in which patients have extremely low levels of circulating HDL, massive accumulation of cholesterol in macrophages, and an increased risk for developing atherosclerosis (Rust S et al. 1999).&lt;p&gt;Multiple microRNAs have been identified as regulators of ABCA1 mRNA levels (Horie T et al. 2010; Sun D et al. 2012; de Aguiar Vallim TQ et al. 2013).</Comment> <BiopaxRef>eaa</BiopaxRef> <BiopaxRef>d23</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1573.0" Y="442.0" /> <Point X="1698.0" Y="442.0" /> <Anchor Position="0.0" Shape="None" GraphId="d48c1" /> <Anchor Position="0.99" Shape="None" GraphId="bf76c" /> <Anchor Position="0.5" Shape="None" GraphId="dea07" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605057" /> </Interaction> <Interaction GraphId="bdcbc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1375.0" Y="396.0" GraphRef="af512" RelX="0.5499999999999545" RelY="0.0" /> <Point X="1378.0" Y="397.0" GraphRef="d727b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029561" /> </Interaction> <Interaction GraphId="be05b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="293.0" Y="799.0" GraphRef="d3573" RelX="-0.009900990099009901" RelY="1.0" /> <Point X="304.0" Y="2496.0" GraphRef="aab9a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029517" /> </Interaction> <Interaction GraphId="be796"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1544.0" Y="1467.0" GraphRef="bae93" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="1554.0" Y="1444.0" GraphRef="dd4f4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031527" /> </Interaction> <Interaction GraphId="bf245"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1703.0" Y="2311.0" GraphRef="f73d2" RelX="0.9500000000000455" RelY="0.2600000000002183" /> <Point X="1706.0" Y="2321.0" GraphRef="d96a3" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608048" /> </Interaction> <Interaction GraphId="bfc16"> <Comment Source="Reactome">Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein particles to triglyceride-rich lipoproteins for subsequent clearance by the liver. CETP expression can be transcriptionally activated by liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) that belong to the nuclear receptor superfamily of ligand-activated transcription factors. Activation of NR1H2,3 induced expression via an LXR response element (LXRE) consisting of 2 hexanucleotide sequences separated by 4 intervening bases (an LXRE of the DR4 type) in the CETP promoter (Luo Y &amp; Tall AR 2000), which may be more responsive to NR1H3 (LXRα) rather than NR1H2 (LXRβ) (Honzumi S et al. 2010). Treatment with T0901317, a synthetic agonist of NR1H2, 3, increased CETP mRNA levels in human liver carcinoma HepG2 cells by approximately 220%, while NR1H3 silencing markedly diminished the increased expression of CETP (Shimada A et al. 2016). It should be noted that CETP is not expressed in the mouse or rat (it is a pseudogene in these species, Hogarth CA et al. 2003), so studies of LXR-mediated regulation of CETP and its effects have been performed in human, hamster, and non-human primates (Groot PHE, et al. 2005).</Comment> <BiopaxRef>a64</BiopaxRef> <BiopaxRef>f39</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1179.0" Y="869.0" /> <Point X="1267.0" Y="869.0" /> <Anchor Position="0.0" Shape="None" GraphId="aa453" /> <Anchor Position="0.99" Shape="None" GraphId="e0cdf" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035133" /> </Interaction> <Interaction GraphId="bff82"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1747.0" Y="2200.0" GraphRef="d93f7" RelX="1.5399999999999636" RelY="0.0" /> <Point X="1750.0" Y="2201.0" GraphRef="f0c04" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605051" /> </Interaction> <Interaction GraphId="bffdd"> <Comment Source="Reactome">The fatty acid synthase (FAS or FASN) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FASN is a central enzyme in de novo lipogenesis. Expression of FASN gene is regulated by the sterol regulatory element-binding transcription factor 1 (SREBP1 or SREBF1) pathway. The FASN promoter was found to be a target for a direct regulation by liver X receptor α (LXRα) and LXRβ (also known as NR1H3 and NR1H2, respectively) (Joseph SB et al. 2002). Agonists of NR1H2 or NR1H3 induced expression of FASN in various mammalian cells including human monocyte-like THP-1 and hepatocellular carcinoma HepG2 cell lines (Joseph SB et al. 2002; Matsukuma KE et al. 2007). In vivo studies showed that mice carrying a targeted disruption in the NR1H3 (LXRα) gene were deficient in expression of FAS, SCD1, and SREBF1 (Peet DJ et al. 1998). The administration of T0901317, a synthetic agonist of NR1H2, NR1H3 upregulated FASN gene expression in both diabetic db/db and nondiabetic C57BLKS mice (Chisholm JW et al. 2003). It also resulted in a more severe hypertriacylglycerolemia and hepatic triacylglycerol accumulation in the db/db diabetic than observed in nondiabetic mice (Chisholm JW et al. 2003). Consistent with in vivo studies, treating HepG2 cells with T0901317 induced lipid accumulation and the expression of lipogenic genes such as FAS, SCD1, and SREBP1c (Li M et al. 2016). </Comment> <BiopaxRef>fab</BiopaxRef> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1572.0" Y="1931.0" /> <Point X="1734.0" Y="1932.0" /> <Anchor Position="0.0" Shape="None" GraphId="f771e" /> <Anchor Position="0.99" Shape="None" GraphId="fc2ba" /> <Anchor Position="0.5" Shape="None" GraphId="f5546" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605063" /> </Interaction> <Interaction GraphId="c0096"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1895.0" Y="1161.0" GraphRef="b9964" RelX="-1.0" RelY="0.0" /> <Point X="1764.0" Y="1107.0" GraphRef="ce9b4" RelX="56.5" RelY="2.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605052" /> </Interaction> <Interaction GraphId="c0585"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1173.0" Y="2504.0" GraphRef="c70a8" RelX="0.9844961240310077" RelY="0.0" /> <Point X="1906.0" Y="2497.0" GraphRef="b0c61" RelX="148.5" RelY="134.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029536" /> </Interaction> <Interaction GraphId="c05e3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1702.0" Y="1140.0" GraphRef="ee82e" RelX="1.7699999999999818" RelY="0.009999999999990905" /> <Point X="1705.0" Y="1141.0" GraphRef="cead6" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035281" /> </Interaction> <Interaction GraphId="c06a8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1493.0" Y="926.0" GraphRef="d443e" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1179.0" Y="869.0" GraphRef="aa453" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035133" /> </Interaction> <Interaction GraphId="c08a4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1556.0" Y="1550.0" GraphRef="ce3d0" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="1566.0" Y="1527.0" GraphRef="d6596" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035279" /> </Interaction> <Interaction GraphId="c092b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1576.0" Y="1017.0" GraphRef="f8540" RelX="0.9710144927536232" RelY="-0.0196078431372549" /> <Point X="1586.0" Y="994.0" GraphRef="c6fc4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624365" /> </Interaction> <Interaction GraphId="c097c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="963.0" Y="1881.0" GraphRef="ab3d7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="c0eab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1487.0" Y="1684.0" GraphRef="f7cdb" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1088.0" Y="1627.0" GraphRef="de0c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657786" /> </Interaction> <Interaction GraphId="c107f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1214.0" Y="1403.0" GraphRef="cf535" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031521" /> </Interaction> <Interaction GraphId="c1c76"> <Comment Source="Reactome">Myosin regulatory light chain interacting protein (MYLIP, aka inducible degrader of the LDLR (IDOL)) is a transcriptional target of the cholesterol-sensing liver X receptors (LXRs, NR1H2 and NR1H3) (Zelcer N et al. 2009, Hong C et al. 2010, Sorrentino V &amp; Zelcer N 2012, Zhang L et al. 2012). LXR agonists induced MYLIP expression in multiple cells in an LXR-dependent manner, including human liver carcinoma HepG2 cells, primary mouse hepatocytes and macrophages (Zelcer N et al. 2009). NR1H2, NR1H3 activate target genes by binding to consensus elements (LXREs) in their promoters. Electrophoretic mobility shift assays coupled with site-directed mutagenesis showed that mouse Mylip (Idol) gene induction occured through binding of the LXR:RXR heterodimer to a functional LXR response element (LXRE) which was identified approximately 2.5 kb upstream of the mouse Mylip (Idol) translation start site (Zelcer et al. 2009). MYLIP (IDOL) functions as an E3 ubiquitin-protein ligase to promote ubiquitylation and lysosomal degradation of the low density lipoprotein receptor (LDLR) (Zelcer N et al. 2009; Zhang et al. 2012; Scotti E et al. 2011; Sorrentino V et al. 2013 a,b). NR1H2 or NR1H3 can increase MYLIP expression, which in turn triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation (Zelcer N et al. 2009, Sorrentino V &amp; Zelcer N 2012, Zhang L et al. 2012). </Comment> <BiopaxRef>b09</BiopaxRef> <BiopaxRef>fe5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1115.0" Y="1564.0" /> <Point X="1259.0" Y="1564.0" /> <Anchor Position="0.0" Shape="None" GraphId="caf5d" /> <Anchor Position="0.99" Shape="None" GraphId="f7eae" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623366" /> </Interaction> <Interaction GraphId="c2509"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1041.0" Y="2389.0" GraphRef="d8595" RelX="0.9831932773109243" RelY="0.0" /> <Point X="1648.0" Y="2418.0" GraphRef="ea7b6" RelX="-196.0" RelY="-0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657775" /> </Interaction> <Interaction GraphId="c269a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1487.0" Y="829.0" GraphRef="abc80" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1177.0" Y="767.0" GraphRef="ca8b0" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029555" /> </Interaction> <Interaction GraphId="c2798"> <Comment Source="Reactome">The phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.</Comment> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1593.0" Y="2200.0" /> <Point X="1747.0" Y="2200.0" /> <Anchor Position="0.0" Shape="None" GraphId="b720d" /> <Anchor Position="0.99" Shape="None" GraphId="d93f7" /> <Anchor Position="0.5" Shape="None" GraphId="cf071" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605051" /> </Interaction> <Interaction GraphId="c2c93"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1825.0" Y="1859.0" GraphRef="af7b4" RelX="0.5599999999999454" RelY="0.03999999999996362" /> <Point X="1828.0" Y="1868.0" GraphRef="a2d7e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618392" /> </Interaction> <Interaction GraphId="c2e82"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1253.0" Y="1210.0" GraphRef="ab3dc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031522" /> </Interaction> <Interaction GraphId="c2eb4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1595.0" Y="2442.0" GraphRef="d1901" RelX="0.979381443298969" RelY="-0.0196078431372549" /> <Point X="1605.0" Y="2419.0" GraphRef="c923c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657775" /> </Interaction> <Interaction GraphId="c30f7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1472.0" Y="1622.0" GraphRef="c7b53" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1115.0" Y="1564.0" GraphRef="caf5d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623366" /> </Interaction> <Interaction GraphId="c33fc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1561.0" Y="2036.0" GraphRef="b387d" RelX="0.9692307692307692" RelY="-0.0196078431372549" /> <Point X="1571.0" Y="2013.0" GraphRef="d3f7f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605060" /> </Interaction> <Interaction GraphId="c3a1b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1191.0" Y="659.0" GraphRef="b0f97" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029521" /> </Interaction> <Interaction GraphId="c3c87"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1821.0" Y="2014.0" GraphRef="f7403" RelX="2.5" RelY="0.009999999999990905" /> <Point X="1824.0" Y="2015.0" GraphRef="b4f38" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605060" /> </Interaction> <Interaction GraphId="c3d7f"> <Comment Source="Reactome">In macrophages, excess of cholesterol leads to the formation of oxysterols, the natural ligands of liver X receptors LXRα (NR1H3) and LXRβ (NR1H2), which belong to the nuclear receptor superfamily of ligand-activated transcription factors. Activation of NR1H2,3 induces expression of ATP-binding cassette transporter A1 (ABCA1), which acts in the plasma membrane and endosomal system to promote cellular cholesterol transfer to lipid-poor apolipoproteins, such as ApoA1 and ApoE associated with high density lipoprotein (HDL) formation (Ignatova ID et al. 2013; Vedhachalam C et a. 2007). NR1H3 (LXRα) was found to be a stronger activator of ABCA1 expression in response to LXR agonists in mouse bone marrow-derived macrophages and in human primary macrophages (Bischoff ED et al. 2010; Ishibashi M et al. 2013). Cholesteryl esters accumulate in various tissues of mice lacking NR1H3, and in cells of the male reproductive system this is directly attributable to reduced expression of ABCA1 (Ouvrier A et al. 2009). Moreover, loss of ABCA1 in humans results in Tangier disease, a condition in which patients have extremely low levels of circulating HDL, massive accumulation of cholesterol in macrophages, and an increased risk for developing atherosclerosis (Rust S et al. 1999). Treatment with the synthetic NR1H2,3 agonist, T0901317, increased expression of ABCA1 mRNA in cells and tissues of wild type, but not NR1H2,3-null mice (Wagner BL et al. 2003; Repa JJ et al. 2000). At the same time, “unligandedâ€� NR1H2,3 repressed basal expression of ABCA1 in a tissue-specific manner, occurring in macrophages and intestinal mucosa but not in several other mouse tissues (Wagner BL et al. 2003). Treatment of human THP-1 macrophages with endogenous (25-hydroxycholesterol) or synthetic (T0901317) NR1H2,3 ligands stimulated both transcriptional and posttranscriptional pathways affecting ABCA1 expression (Ignatova ID et al. 2013).&lt;p&gt;NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF &amp; Gustafsson JA 1997). The human ABCA1 promoter was found to contain a LXRE located about 50 bp upstream of the transcription start site (Costet P et al. 2000). Gel shift experiments showed that NR1H2,3:RXR heterodimers bind to the isolated LXREs from human ABCA1 (Costet P et al. 2000). Further, the ligand-selective regulation of ABCA1 was observed when ABCA1 promoter-luciferase reporter constructs were transfected into human embryonic kidney 293T cells or human liver carcinoma HepG2 cells that were then treated with T0901317 or 25-hydroxycholesterol to show enhanced luciferase activity (Ignatova ID et al. 2013). Unliganded LXR:RXR actively suppresses transcription by recruiting a corepressor complex. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interaction domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT or NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). The chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of RXR in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (Jakobsson T et al. 2009).</Comment> <BiopaxRef>eaa</BiopaxRef> <BiopaxRef>b89</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="619.0" Y="403.0" /> <Point X="698.0" Y="402.0" /> <Anchor Position="0.0" Shape="None" GraphId="c3823" /> <Anchor Position="0.99" Shape="None" GraphId="d835e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024326" /> </Interaction> <Interaction GraphId="c3f5f"> <Comment Source="Reactome">The ATP-binding cassette (ABC) transporter 5 (ABCG5) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mammalian cells, ABCG8 and ABCG5 form obligate heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for developing premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001). In the pathogenesis of cholesterol gallstone disease, the upregulation of ABCG5 and ABCG8 in gallstone patients, possibly mediated by increased NR1H3 (LXRα), may contribute to the cholesterol supersaturation of bile (Jiang ZY et al. 2008). As shown in mice, both Abcg8 and Abcg5 are target genes of the liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) (Repa JJ et al. 2002; van der Veen et al. 2007). The synthetic LXR agonist, T0901317, markedly upregulated Abcg5 and Abcg8 mRNA levels in the small intestine and liver of wild type but not NR1H3 knockout mice (Repa JJ et al. 2002; van der Veen et al. 2007; Yu L et al. 2003). The human ABCG8 and ABCG5 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species (Remaley AT et al. 2002). This intergenic region acts as a bidirectional promoter, and harbors potential binding sites for hepatocyte nuclear factor 4α (HNF4α), liver receptor homolog 1 (LRH1) and GATA transcription factors (Remaley AT et al. 2002; Sumi K et al. 2007; Freeman LA et al. 2004). Regarding sterol/LXRs regulation of ABCG5, electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated the binding of NR1H3 to two intronic regions of the human ABCG8 gene to confer NR1H3-mediated regulation in human liver carcinoma HepG2 cells (Back SS et al. 2013).</Comment> <BiopaxRef>c9e</BiopaxRef> <BiopaxRef>db4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1575.0" Y="701.0" /> <Point X="2015.0" Y="702.0" /> <Anchor Position="0.0" Shape="None" GraphId="b279c" /> <Anchor Position="0.99" Shape="None" GraphId="f8df7" /> <Anchor Position="0.5" Shape="None" GraphId="daeb8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029531" /> </Interaction> <Interaction GraphId="c415e"> <Comment Source="Reactome">Expression of the ATP-binding cassette transporter A1 (ABCA1) gene is induced by oxysterol-activated transcription factors liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) and their heterodimeric partners, retinoid X receptors (RXR) via functional LXR response element (LXRE) (Costet P et al. 2000; Ignatova ID et al. 2013). NR1H2, 3-induced expression of ABCA1 is thought to promote ABCA1-mediated cellular cholesterol transport across the plasma membrane to lipid poor apolipoproteins, such as ApoA1 and ApoE in the generation of nascent HDL particles (Vedhachalam C et a. 2007; Ignatova ID et al. 2013). MicroRNA (miR-144) was found to bind the 3'-untranslated region (3'UTR) of ABCA1 mRNA to prohibit translation and reduce ABCA1-mediated cholesterol efflux from hepatocytes (de Aguiar Vallim TQ et al. 2013). In the liver, the farnesoid X receptor (FXR or NR1H4) often acts in opposition to LXRs in the regulation of cholesterol homeostasis. Indeed, FXR activation increases miR-144 expression to decrease hepatic ABCA1 levels and reduce circulating HDL concentrations in mouse models (de Aguiar Vallim TQ et al. 2013). Further, overexpression of miR-144 in a human hepatoma cell line (Hep3B) resulted in a decrease in both ABCA1 protein and efflux of cholesterol to lipid-poor ApoA-I, in the absence of a change in ABCA1 mRNA (de Aguiar Vallim TQ et al. 2013). Hepatic ABCA1 activity is responsible for ~75% of circulating HDL levels (with adipose and intestine contributing to the remainder). While macrophage ABCA1 activity is important in limiting foam cell formation during atherogenesis, macrophage ABCA1-generated HDL particles are not sufficiently abundant to significantly impact the circulating HDL pool. Of note, FXR is not expressed in macrophages, thus FXR/miR-144 is unlikely to contribute greatly to foam cell formation in atherogenesis, but FXR/miR-144 will more dramatically alter circulating serum HDL concentrations through its actions in the liver (de Aguiar Vallim TQ et al. 2013). </Comment> <BiopaxRef>a42</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1816.0" Y="272.0" /> <Point X="1898.0" Y="272.0" /> <Anchor Position="0.0" Shape="None" GraphId="a8812" /> <Anchor Position="0.99" Shape="None" GraphId="be9a7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657791" /> </Interaction> <Interaction GraphId="c416c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1892.0" Y="1162.0" GraphRef="c2b92" RelX="0.5099999999999909" RelY="-0.01999999999998181" /> <Point X="1895.0" Y="1161.0" GraphRef="b9964" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9038545" /> </Interaction> <Interaction GraphId="c4691"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="293.0" Y="799.0" GraphRef="d3573" RelX="-0.009900990099009901" RelY="1.0" /> <Point X="662.0" Y="2389.0" GraphRef="e1c7e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657836" /> </Interaction> <Interaction GraphId="c4e5a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="380.0" Y="2497.0" GraphRef="e4531" RelX="0.7599999999999909" RelY="0.010000000000218279" /> <Point X="383.0" Y="2497.0" GraphRef="c9987" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029517" /> </Interaction> <Interaction GraphId="c4f72"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1434.0" Y="1162.0" GraphRef="bd785" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1259.0" Y="1113.0" GraphRef="cdec9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035185" /> </Interaction> <Interaction GraphId="c50a7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1497.0" Y="2036.0" GraphRef="b387d" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="924.0" Y="1970.0" GraphRef="db076" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="c5a0e"> <Comment Source="Reactome">Apolipoprotein C4 (APOC4) is present in the APOE, APOC1, APOC4 and APOC2-gene cluster which is induced by natural and synthetic ligands of liver X receptors (LXRα, NR1H3 and LXRβ, NR1H2) in both human and mouse macrophages (Mak PA et al. 2002). The induction of all four mRNAs was greatly attenuated in macrophages derived from LXR α/β-/- mice (Mak PA et al. 2002). Cell reporter assays suggest that the LXR response elements (LXRE) in the multienhancer regions ME.1 and ME.2, which confer tissue-specific expression in macrophages and adipocytes (Shih SJ et al. 2000), are necessary for the expression of this gene cluster (Mak PA et al. 2002). 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In the unliganded state, LXR:RXR heterodimers are bound to DNA response elements in association with co-repressor complexes resulting in repression of target genes (Wagner BL et al. 2003). Ligand binding to LXR induces conformational changes leading to release of co-repressor complexes and recruitment of co-activator complexes and transcription of target genes.</Comment> <BiopaxRef>b21</BiopaxRef> <BiopaxRef>aba</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="515.0" Y="2496.0" /> <Point X="567.0" Y="2496.0" /> <Anchor Position="0.0" Shape="None" GraphId="edef1" /> <Anchor Position="0.99" Shape="None" GraphId="e04a8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029566" /> </Interaction> <Interaction GraphId="c9df8"> <Comment Source="Reactome">Cell-based and in vivo studies using mice showed that the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8 genes are direct targets of the oxysterol-activated liver X receptor alpha (LXRα or NR1H3) and LXRβ (NR1H2) (Repa JJ et al. 2002; Berge KE et al. 2000). The LXR agonist T0901317 markedly upregulated mRNA levels of Abcg5 and Abcg8 in the small intestine and liver of wild type (WT), but not NR1H3 or NR1H3/H2- knockout mice (Repa JJ et al. 2002; van der Veen et al. 2007). Further, treatment with T0901317 increased fecal neutral sterol excretion from WT, but not Abcg5-/- mice (Plösch T et al. 2006). These data suggest that in the intestine, activation of NR1H2,3 leads to the upregulation of the transmembrane transporters ABCG5 and ABCG8 resulting in decreased intestinal sterol absorption. The human ABCG5 and ABCG8 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species. Using a reporter construct, the intergenic region was found to act as a bidirectional promoter (Remaley AT et al. 2002). Through elaborate deletion studies, two LXR response elements (LXRE) were identified in intronic regions of the human ABCG8 gene to confer sterol regulation of ABCG5 and ABCG8 genes (Back SS et al. 2013). Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated the binding of NR1H3 to these LXRE regions in the nuclei of human liver cancer HepG2 cells (Back SS et al. 2013).&lt;p&gt;In mammalian cells, ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001).</Comment> <BiopaxRef>c9e</BiopaxRef> <BiopaxRef>db4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1191.0" Y="659.0" /> <Point X="1266.0" Y="660.0" /> <Anchor Position="0.0" Shape="None" GraphId="b0f97" /> <Anchor Position="0.99" Shape="None" GraphId="af0ed" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029521" /> </Interaction> <Interaction GraphId="c9e41"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1205.0" Y="959.0" GraphRef="acd9e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624353" /> </Interaction> <Interaction GraphId="c9f30"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1113.0" Y="1707.0" GraphRef="b0248" RelX="0.5" RelY="0.0" /> <Point X="1116.0" Y="1707.0" GraphRef="a6c2d" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035167" /> </Interaction> <Interaction GraphId="ca0ca"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="892.0" Y="400.0" GraphRef="b8f8c" RelX="0.6100000000000136" RelY="0.0" /> <Point X="908.0" Y="444.0" GraphRef="d9b89" RelX="-0.008849557522123894" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024334" /> </Interaction> <Interaction GraphId="ca168"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1799.0" Y="442.0" GraphRef="f609b" RelX="0.9797979797979798" RelY="0.0" /> <Point X="1803.0" Y="442.0" GraphRef="ea304" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618479" /> </Interaction> <Interaction GraphId="ca380"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="523.0" Y="2175.0" GraphRef="f85c7" RelX="0.9746835443037974" RelY="0.0" /> <Point X="845.0" Y="2174.0" GraphRef="bc8b3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="ca891"> <Comment Source="Reactome">The ADP-ribosylation factor-like 4C (ARL4C or ARL7) mRNA is translated to yield ARL4C protein. ARL4C localizes to both the cell surface membrane and nucleus; however, a GDP-restricted mutant (Arl4c T27N) is mainly distributed in the cytoplasm (Engel T et al. 2004; Heo WD et al. 2006). Further, mutant constructs showed that effective plasma membrane targeting of ARL4C required an N-terminal myristoyl motif as well as a flexible C-terminal polybasic tail, which suggests that the two ends of the protein synergistically support cell surface targeting (Heo WD et al. 2006).&lt;p&gt;Cholesterol-loading or treatment with the synthetic agonists of liver X-receptors alpha (LXRα, NR1H3) and beta (LXRβ, NR1H2), such as T0901317 or GW3965, signiï¬�cantly induced the expression of ARL4C in murine RAW 264.7 and human THP1 macrophage cell lines (Hong C et al. 2011; Engel T et al. 2004; Sun D et al. 2012). Similar regulation of ARL4C mRNA expression was observed in human peripheral blood-derived monocytes (Hong C et al. 2011). NR1H2 or NR1H3 stimulation ARL4C has been shown to transport cholesterol to the membrane for the ATP-binding cassette transporter A1 (ABCA1)-associated cholesterol removal (Engel T et al. 2004). Overexpression of ARL4C in HeLa cells has been shown to enhance APOA1-mediated cholesterol efflux (Engel T et al. 2004). MicroRNA miR-26 represses NR1H2,3-dependent cholesterol efflux by targeting ARL4C mRNA (Sun D et al. 2012). </Comment> <BiopaxRef>c88</BiopaxRef> <BiopaxRef>c6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1843.0" Y="1823.0" /> <Point X="1923.0" Y="1824.0" /> <Anchor Position="0.0" Shape="None" GraphId="b8c7b" /> <Anchor Position="0.99" Shape="None" GraphId="fec70" /> <Anchor Position="0.5" Shape="None" GraphId="f1340" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618405" /> </Interaction> <Interaction GraphId="ca900"> <Comment Source="Reactome">Translation of liver X receptor α (LXRα or NR1H3) mRNA is negatively regulated by microRNA 613 (miR-613), which binds directly to the specific miRNA response element (613MRE) within the 3'UTR of NR1H3 mRNA (Ou Z et al. 2011; Zhong D et al. 2013). The expression of miR-613 itself was induced upon the activation of NR1H3. However, miR-613 did not appear to be a direct NR1H3 target gene (Ou Z et al. 2011). Instead, the positive regulation of miR-613 by NR1H3 was mediated by the sterol regulatory element binding protein (SREBP)-1c, a known NR1H2,3 target gene (Ou Z et al. 2011). The binding of miR-613 to NR1H3 mRNA repressed lipogenesis in human liver carcinoma HepG2 cells and this was reversed by NR1H3 overexpression (Zhong D et al. 2013).</Comment> <BiopaxRef>dc5</BiopaxRef> <BiopaxRef>c16</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1841.0" Y="1164.0" /> <Point X="1892.0" Y="1162.0" /> <Anchor Position="0.0" Shape="None" GraphId="ba4ec" /> <Anchor Position="0.99" Shape="None" GraphId="c2b92" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9038545" /> </Interaction> <Interaction GraphId="cb1c9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1499.0" Y="2442.0" GraphRef="d1901" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="662.0" Y="2389.0" GraphRef="e1c7e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657836" /> </Interaction> <Interaction GraphId="cb2c7"> <Comment Source="Reactome">The liver X receptor alpha (LXRα or NR1H3) mRNA is translated to yield NR1H3 protein. MicroRNAs miR-1, miR-206 and miR-613 have been identified as negative regulators of NR1H3 expression and lipogenesis in the liver (Zhong D et al. 2013; Ou Z et al. 2011). Interestingly, miR-206 also regulates NR1H3 in macrophages but in an opposing manner relative to liver (Vinod M et al. 2014). Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation of NR1H3 and miR-206 knockdown led to a down-regulation of NR1H3 and its target genes (Vinod M et al. 2014).</Comment> <BiopaxRef>c16</BiopaxRef> <BiopaxRef>dc5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1764.0" Y="1127.0" /> <Point X="1651.0" Y="1082.0" /> <Anchor Position="0.0" Shape="None" GraphId="cdf10" /> <Anchor Position="0.99" Shape="None" GraphId="af8bd" /> <Anchor Position="0.5" Shape="None" GraphId="ce9b4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605052" /> </Interaction> <Interaction GraphId="cbcf1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1259.0" Y="1564.0" GraphRef="f7eae" RelX="1.4400000000000546" RelY="0.0" /> <Point X="1262.0" Y="1564.0" GraphRef="abff4" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623366" /> </Interaction> <Interaction GraphId="cc40c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1042.0" Y="2503.0" GraphRef="e240e" RelX="2.0" RelY="0.01999999999998181" /> <Point X="1045.0" Y="2504.0" GraphRef="c70a8" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029580" /> </Interaction> <Interaction GraphId="ccb30"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1716.0" Y="1832.0" GraphRef="e9429" RelX="1.3700000000001182" RelY="-0.07999999999992724" /> <Point X="1719.0" Y="1824.0" GraphRef="a5faa" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618394" /> </Interaction> <Interaction GraphId="cceff"> <Comment Source="Reactome">The APOC1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.&lt;p&gt;Ligand-activated liver X receptors (LXRα, NR1H3 and LXRβ NR1H2) induce expression of a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 in both human and mouse macrophages (Mak PA et al. 2002). Induction of APOC2 mRNA was attenuated or abolished in macrophages derived from LXR α/β-/- mice (Mak PA et al. 2002).</Comment> <BiopaxRef>db5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1553.0" Y="1350.0" /> <Point X="2086.0" Y="1342.0" /> <Anchor Position="0.0" Shape="None" GraphId="f293b" /> <Anchor Position="0.99" Shape="None" GraphId="f5e5f" /> <Anchor Position="0.5" Shape="None" GraphId="b298f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031510" /> </Interaction> <Interaction GraphId="cdf35"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1171.0" Y="1489.0" GraphRef="c129d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035143" /> </Interaction> <Interaction GraphId="ce684"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="365.0" GraphRef="c3e9f" RelX="-1.9298245614035088" RelY="2.3333333333333335" /> <Point X="1901.0" Y="442.0" GraphRef="a644b" RelX="-9.5" RelY="0.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618479" /> </Interaction> <Interaction GraphId="ce8b7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1979.0" Y="495.0" GraphRef="bd085" RelX="0.9764705882352941" RelY="0.0" /> <Point X="2032.0" Y="490.0" GraphRef="b2154" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9619756" /> </Interaction> <Interaction GraphId="cf4b7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1497.0" Y="616.0" GraphRef="baf9c" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1190.0" Y="551.0" GraphRef="bdca9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="cf6ad"> <Comment Source="Reactome">Micro RNA miR-26 was identified as a liver X receptor (LXR or NR1H2,3)-repressed miRNA in macrophage cell lines (Sun D et al. 2012). miR-26 suppressed translation of ATP-binding cassette transporter A1 (ABCA1) mRNA in NR1H2,3 (LXR)â€�activated human (THP-1) and mouse (RAW264.7) macrophage cell lines. Bioinformatic tools for miRNA target prediction identified a highly conserved seed regions for miRâ€�26a and miRâ€�26b in the 3′UTR of the ABCA1 transcript that was confirmed by 3’UTR luciferase assay methods (Sun D et al. 2012). Moreover, miRâ€�26 was shown to reduce cellular ABCA1 protein levels and abrogate NR1H2,3â€�dependent cholesterol efflux in RAW264.7 cells by targeting ABCA1 and ARL4C (ARL7) mRNA (Sun D et al. 2012). Conversely, treating RAW cells with miR-26 inhibitors, increased ABCA1 protein levels, and enhanced LXR agonist-mediated cholesterol efflux (Sun D et al. 2012). TheThe Reactome event describes the miR-26- regulated translation of ABCA1 mRNA in response to NR1H2,3 natural ligands. The annotation is based on the study with GW3965 and T0901317, the synthetic agonists of NR1H2,3 (Sun D et al. 2012).</Comment> <BiopaxRef>c88</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1786.0" Y="323.0" /> <Point X="1870.0" Y="322.0" /> <Anchor Position="0.0" Shape="None" GraphId="d7da2" /> <Anchor Position="0.99" Shape="None" GraphId="adbe7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618486" /> </Interaction> <Interaction GraphId="cf746"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1484.0" Y="724.0" GraphRef="b6012" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1191.0" Y="659.0" GraphRef="b0f97" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029521" /> </Interaction> <Interaction GraphId="cfc99"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1397.0" Y="549.0" GraphRef="f0e60" RelX="1.0" RelY="0.0" /> <Point X="1626.0" Y="594.0" GraphRef="b631f" RelX="-178.5" RelY="0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024361" /> </Interaction> <Interaction GraphId="d0205"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1563.0" Y="926.0" GraphRef="d443e" RelX="0.971830985915493" RelY="-0.0196078431372549" /> <Point X="1573.0" Y="903.0" GraphRef="c23a2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035169" /> </Interaction> <Interaction GraphId="d15c2"> <Comment Source="Reactome">The ATP-binding cassette sub-family G member 8 (ABCG8) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mammalian cells, ABCG8 and ABCG5 form obligate heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for developing premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001). In the pathogenesis of cholesterol gallstone disease, the upregulation of ABCG5 and ABCG8 in gallstone patients, possibly mediated by increased NR1H3 (LXRα), may contribute to the cholesterol supersaturation of bile (Jiang ZY et al. 2008). As shown in mice, both Abcg8 and Abcg5 are target genes of the liver X receptor α (LXRα, NR1H3) and can be induced by LXRs agonists (Repa JJ et al. 2002; Yu L et al. 2003). The human ABCG8 and ABCG5 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species (Remaley AT et al. 2002). The luciferase reporter assay in human liver carcinoma HepG2 cells revealed that the intergenic region of ABCG5 and ABCG8 genes acted as a bidirectional promoter, and contained binding sites for hepatocyte nuclear factor 4α (HNF4α), liver receptor homolog 1 (LRH1) and GATA transcription factors (Remaley AT et al. 2002; Sumi K et al. 2007; Freeman LA et al. 2004). Further, electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP) (ChIP), and cell reporter assays demonstrated the binding of NR1H3 to two intronic regions of the human ABCG8 gene to confer LXR-mediated regulation of ABCG5 and ABCG8 genes in HepG2 cells (Back SS et al. 2013). Finally, co-expression of the pABCG8-LUC reporter plasmid with an appropriate combination of the expression plasmids of five transcription factors, NR1H3 (LXRα), RXRα, GATA4, HNF4α, and LRH-1 in the HepG2 cells showed synergistic transcriptional activation of ABCG8 gene (Back SS et al. 2013).</Comment> <BiopaxRef>c9e</BiopaxRef> <BiopaxRef>db4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1578.0" Y="806.0" /> <Point X="2024.0" Y="805.0" /> <Anchor Position="0.0" Shape="None" GraphId="e6925" /> <Anchor Position="0.99" Shape="None" GraphId="b25f5" /> <Anchor Position="0.5" Shape="None" GraphId="cf1e4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029591" /> </Interaction> <Interaction GraphId="d1bb1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1402.0" Y="871.0" GraphRef="f1e10" RelX="1.0" RelY="0.0" /> <Point X="1619.0" Y="905.0" GraphRef="fde8b" RelX="-208.5" RelY="1.5" ArrowHead="Arrow" /> 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RelY="0.0" /> <Point X="1701.0" Y="442.0" GraphRef="f609b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605057" /> </Interaction> <Interaction GraphId="d4cb1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1817.0" Y="1183.0" GraphRef="a9317" RelX="-0.01098901098901099" RelY="-1.0" /> <Point X="1841.0" Y="1164.0" GraphRef="ba4ec" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9038545" /> </Interaction> <Interaction GraphId="d50c6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1056.0" Y="2321.0" GraphRef="ae3bd" RelX="0.9813084112149533" RelY="0.0" /> <Point X="1651.0" Y="2361.0" GraphRef="cb53c" RelX="-6.0" RelY="-11.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9607342" /> </Interaction> <Interaction GraphId="d52b8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1584.0" Y="2223.0" GraphRef="adfbb" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1593.0" Y="2200.0" GraphRef="b720d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605051" /> </Interaction> <Interaction GraphId="d5cec"> <Comment Source="Reactome">In the unliganded state, NR1H2,3 (LXR):RXR heterodimers are bound to DNA response elements in association with co-repressor complexes resulting in repression of target genes such as the ATP-binding cassette transporter (ABCA1) gene (Wagner BL et al. 2003; Jakobsson T et al. 2009). Ligand binding to NR1H2,3 induces conformational changes leading to release of co-repressor complexes and recruitment of co-activator complexes and transcription of target genes. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interacting domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT, also known as NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in the monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). Chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with the ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of anti-RXR antibody in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (Jakobsson T et al. 2009).</Comment> <BiopaxRef>aba</BiopaxRef> <BiopaxRef>eaa</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="831.0" Y="400.0" /> <Point X="892.0" Y="400.0" /> <Anchor Position="0.0" Shape="None" GraphId="b2fdc" /> <Anchor Position="0.99" Shape="None" GraphId="b8f8c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024334" /> </Interaction> <Interaction GraphId="d6018"> <Comment Source="Reactome">The ileal bile acid-binding protein (I-BABP, also known as FABP6) is a 14 kDa soluble bile acid (BA) carrier protein which belongs to the fatty acid-binding protein (FABP) family. FABP6 gene expression was directly up-regulated by liver X-receptor α (LXRα or NR1H3) and LXRβ (NR1H2) in human enterocyte-like Caco-2 cells when the cells were transiently cotransfected with a FABP6 promoter fragment cloned upstream of the CAT reporter gene and expression vectors for NR1H3 or NR1H2 and retinoid X receptor α (RXRα) (Landrier JF et al. 2003). Electrophoretic mobility shift assays demonstrated that the NR1H3:RXR heterodimer specifically recognized a farnesoid Xâ€�receptorâ€�responsive element (FXRE) which functioned as an LXR responsive element (LXRE) in the promoter of FABP6 gene (Landrier JF et al. 2003). Similar data have been reported for the PLTP gene suggesting that the FXRE sequence can function as an LXRâ€�binding site in different genes (Landrier JF et al. 2002). FABP6 gene expression can be also up-regulated by sterol sensors such as farnesoid X receptor (FXR, NR1H4) or sterol-responsive element-binding protein 1c (SREBP1c) (Mak PA et al. 2002; Landrier JF et al. 2002; Zaghini I et al. 2002).</Comment> <BiopaxRef>ced</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="720.0" Y="2323.0" /> <Point X="947.0" Y="2322.0" /> <Anchor Position="0.0" Shape="None" GraphId="ffb0b" /> <Anchor Position="0.99" Shape="None" GraphId="e7e6c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9631296" /> </Interaction> <Interaction GraphId="d6173"> <Comment Source="Reactome">The APOC4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.&lt;p&gt;Ligand-activated liver X receptors (LXRα, NR1H3 and LXRβ NR1H2) induce expression of a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 in both human and mouse macrophages (Mak PA et al. 2002). The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXR α/β-/- mice (Mak PA et al. 2002). Cel reporter assays suggest that the LXR response elements (LXRE) in the multienhancer regions ME.1 and ME.2, which confer tissue-specific expression in macrophages and adipocytes (Shih SJ et al. 2000), are necessary for the expression of this gene cluster (Mak PA et al. 2002). These secreted apolipoproteins regulate lipid transport and catabolism.</Comment> <BiopaxRef>db5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1566.0" Y="1527.0" /> <Point X="2085.0" Y="1523.0" /> <Anchor Position="0.0" Shape="None" GraphId="d6596" /> <Anchor Position="0.99" Shape="None" GraphId="b165d" /> <Anchor Position="0.5" Shape="None" GraphId="b2f39" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035279" /> </Interaction> <Interaction GraphId="d7399"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1487.0" Y="1769.0" GraphRef="d7ab5" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1063.0" Y="1707.0" GraphRef="c4a56" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035167" /> </Interaction> <Interaction GraphId="d7a16"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="920.0" Y="2389.0" GraphRef="b6a8e" RelX="2.580000000000041" RelY="0.0" /> <Point X="923.0" Y="2389.0" GraphRef="d8595" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657836" /> </Interaction> <Interaction GraphId="d7b64"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1159.0" Y="399.0" GraphRef="d7645" RelX="0.6199999999998909" RelY="0.0" /> <Point X="1162.0" Y="401.0" GraphRef="de15a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029551" /> </Interaction> <Interaction GraphId="d87ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2082.0" Y="904.0" GraphRef="cd741" RelX="5.0900000000001455" RelY="0.009999999999990905" /> <Point X="2085.0" Y="904.0" GraphRef="ba607" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035169" /> </Interaction> <Interaction GraphId="d9275"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="963.0" Y="1881.0" GraphRef="ab3d7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="d9313"> <Comment Source="Reactome">The agonists of liver X receptors (LXRs, NR1H2 and NR1H3) increased expression of myosin regulatory light chain interacting protein (MYLIP aka inducible degrader of the LDLR (IDOL)) in multiple cells in an LXR-dependent manner, including human liver carcinoma HepG2 cells, primary mouse hepatocytes and macrophages (Zelcer N et al. 2009; Hong C et al. 2010, Sorrentino V &amp; Zelcer N 2012, Zhang L et al. 2012).&lt;p&gt;MYLIP (IDOL) functions as an E3 ubiquitin-protein ligase to promote ubiquitylation of the low density lipoprotein receptor (LDLR) (Zelcer N et al. 2009; Zhang et al. 2012; Scotti E et al. 2011; Sorrentino V et al. 2013 a,b). LDLR is expressed primarily in liver and removes cholesterol-carrying LDL from plasma by receptor-mediated endocytosis (Brown MS &amp; Goldstein JL 1986). Once ubiquitylated, LDLR is rapidly removed from the plasma membrane and sorted by the ESCRT (endosomal sorting complexes required for transport) machinery toward the lysosome for degradation (Sorrentino V et al. 2013a,b; Scotti E et al. 2013). The cholesterol-sensing NR1H2 and NR1H3 can increase MYLIP expression, which in turn triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby regulating cholesterol uptake (Zelcer N et al. 2009, Sorrentino V &amp; Zelcer N 2012, Zhang L et al. 2012). </Comment> <BiopaxRef>fe5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1556.0" Y="1599.0" /> <Point X="1735.0" Y="1596.0" /> <Anchor Position="0.0" Shape="None" GraphId="d8d81" /> <Anchor Position="0.99" Shape="None" GraphId="ea990" /> <Anchor Position="0.5" Shape="None" GraphId="f72f5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623365" /> </Interaction> <Interaction GraphId="d947e"> <Comment Source="Reactome">The liver X receptor alpha (LXRα or NR1H3) gene is transcribed to yield mRNA. The NR1H3 gene expression is auto-inducible ((Whitney KD et al. 2001; Laffitte BA et al. 2001; Li Y et al. 2002). NR1H3 (LXRα) induction was observed in multiple human cell types including monocyte-derived macrophages, the THP1 macrophage cell line and skin fibroblasts in response to NR1H3 and NR1H2 (LXRβ) ligands (20(S)hydroxycholesterol, 22(R)hydroxycholesterol, 24(S),25-epoxycholesterol,&lt;br&gt;GW3965 or T0901317) (Whitney KD et al. 2001; Laffitte BA et al. 2001; Li Y et al. 2002). This induction was mediated via LXR response elements (LXREs) found within the NR1H3 promoter ((Whitney KD et al 2001; Laffitte BA et al. 2001; Li Y et al. 2002). The autoregulatory loop led to the selective induction of NR1H3 gene expression whereas NR1H2 (LXRβ) was not induced (Whitney KD et al. 2001; Lafitte B et al. 2001; Li Y et al. 2002). The increased NR1H3 levels induce expression of its downstream target genes such as ABCA1, ABCG1 providing a simple yet exquisite mechanism for cells to respond to LXRs ligands and cholesterol loading (Li Y et al. 2002).</Comment> <BiopaxRef>daa</BiopaxRef> <BiopaxRef>b59</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1525.0" Y="1139.0" /> <Point X="1702.0" Y="1140.0" /> <Anchor Position="0.0" Shape="None" GraphId="d14f3" /> <Anchor Position="0.99" Shape="None" GraphId="ee82e" /> <Anchor Position="0.5" Shape="None" GraphId="b4cd9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035281" /> </Interaction> <Interaction GraphId="d9dfa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1651.0" Y="1082.0" GraphRef="af8bd" RelX="-1.1300000000001091" RelY="-0.4500000000000455" /> <Point X="1648.0" Y="1077.0" GraphRef="fe2cb" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605052" /> </Interaction> <Interaction GraphId="d9e80"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1563.0" Y="1954.0" GraphRef="e59ec" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1572.0" Y="1931.0" GraphRef="f771e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605063" /> </Interaction> <Interaction GraphId="d9ec4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1399.0" Y="767.0" GraphRef="cf185" RelX="1.0" RelY="0.0" /> <Point X="1626.0" Y="805.0" GraphRef="cf1e4" RelX="-175.0" RelY="-0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029591" /> </Interaction> <Interaction GraphId="da4fd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="365.0" GraphRef="e9c14" RelX="-2.3388429752066116" RelY="5.166666666666667" /> <Point X="1901.0" Y="442.0" GraphRef="a644b" RelX="-9.5" RelY="0.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618479" /> </Interaction> <Interaction GraphId="da785"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="767.0" Y="2252.0" GraphRef="bc193" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608039" /> </Interaction> <Interaction GraphId="daa5a"> <Comment Source="Reactome">The APOC2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.&lt;p&gt;Ligand-activated liver X receptors (LXRα, NR1H3 and LXRβ NR1H2) induce expression of a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 in both human and mouse macrophages (Mak PA et al. 2002). The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXR α/β-/- mice (Mak PA et al. 2002). Cel reporter assays suggest that the LXR response elements (LXRE) in the multienhancer regions ME.1 and ME.2, which confer tissue-specific expression in macrophages and adipocytes (Shih SJ et al. 2000), are necessary for the expression of this gene cluster (Mak PA et al. 2002). These secreted apolipoproteins regulate lipid transport and catabolism.</Comment> <BiopaxRef>db5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1554.0" Y="1444.0" /> <Point X="2083.0" Y="1437.0" /> <Anchor Position="0.0" Shape="None" GraphId="dd4f4" /> <Anchor Position="0.99" Shape="None" GraphId="d60be" /> <Anchor Position="0.5" Shape="None" GraphId="a7675" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031527" /> </Interaction> <Interaction GraphId="daca8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1776.0" Y="1877.0" GraphRef="f3086" RelX="0.9759036144578314" RelY="0.0" /> <Point X="1769.0" Y="1855.0" GraphRef="e1e27" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618392" /> </Interaction> <Interaction GraphId="db134"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1177.0" Y="767.0" GraphRef="ca8b0" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029555" /> </Interaction> <Interaction GraphId="dbcbf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="827.0" Y="402.0" GraphRef="ae611" RelX="0.984251968503937" RelY="0.0" /> <Point X="831.0" Y="400.0" GraphRef="b2fdc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024334" /> </Interaction> <Interaction GraphId="dbf35"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1516.0" Y="1162.0" GraphRef="bd785" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1525.0" Y="1139.0" GraphRef="d14f3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035281" /> </Interaction> <Interaction GraphId="dc051"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1491.0" Y="1954.0" GraphRef="e59ec" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="963.0" Y="1881.0" GraphRef="ab3d7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="dc3d1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2085.0" Y="1523.0" GraphRef="b165d" RelX="5.190000000000055" RelY="-0.03999999999996362" /> <Point X="2088.0" Y="1523.0" GraphRef="e1e84" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035279" /> </Interaction> <Interaction GraphId="dc7c1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="931.0" Y="2249.0" GraphRef="a2394" RelX="1.6399999999999864" RelY="-0.03000000000020009" /> <Point X="934.0" Y="2248.0" GraphRef="b0a40" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608039" /> </Interaction> <Interaction GraphId="dca11"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1779.0" Y="1843.0" GraphRef="a5faa" RelX="-0.008264462809917356" RelY="1.0" /> <Point X="1769.0" Y="1855.0" GraphRef="e1e27" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618392" /> </Interaction> <Interaction GraphId="dce83"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1905.0" Y="2229.0" GraphRef="c8e0f" RelX="2.9500000000000455" RelY="-2.6799999999998363" /> <Point X="1905.0" Y="2226.0" GraphRef="a3a41" RelX="-0.01694915254237288" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029536" /> </Interaction> <Interaction GraphId="dd0ae"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1063.0" Y="1707.0" GraphRef="c4a56" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035167" /> </Interaction> <Interaction GraphId="de08f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="261.0" Y="2494.0" GraphRef="ccec8" RelX="0.984251968503937" RelY="0.0" /> <Point X="304.0" Y="2496.0" GraphRef="aab9a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029517" /> </Interaction> <Interaction GraphId="de82e"> <Comment Source="Reactome">Activation of liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) induces expression of ATP-binding cassette transporter A1 (ABCA1) (Jakobsson T et al. 2009). NR1H2,3 form functional dimers with retinoid X receptors (RXR) that bind to LXR-response elements (LXREs) in the DNA of target genes (Wiebel FF &amp; Gustafsson JA 1997). Nuclear receptor coactivator 1 (NCOA1, also known as SRC1) binds to the ABCA1 gene promoter via oxysterol-induced NR1H3:RXR heterodimer (Huuskonen J et al. 2004). NCOA1 recruits E1A-associated protein p300 (EP300 or p300) leading to a maximal activation of ABCA1 promoter activity (Huuskonen J et al. 2004). EP300 are homologous coactivators capable of binding to the AD1 domain of p160 coactivators such as NCOA1. &lt;p&gt;EP300, NCOA1 and other members of the p160 coactivator complex contribute to active chromatin structures via coactivator binding activity, acetylation or methylation of histones and other components of the transcription unit (reviewed in Xu J &amp; Li Q 2003; Xu L et al. 2009; Chan HM &amp; La Thangue NB 2001). </Comment> <BiopaxRef>d23</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1320.0" Y="396.0" /> <Point X="1375.0" Y="396.0" /> <Anchor Position="0.0" Shape="None" GraphId="eed89" /> <Anchor Position="0.99" Shape="None" GraphId="af512" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029561" /> </Interaction> <Interaction GraphId="dece5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="947.0" Y="2322.0" GraphRef="e7e6c" RelX="2.269999999999982" RelY="-0.010000000000218279" /> <Point X="950.0" Y="2321.0" GraphRef="ae3bd" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9631296" /> </Interaction> <Interaction GraphId="dede2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1546.0" Y="1622.0" GraphRef="c7b53" RelX="0.9733333333333334" RelY="-0.0196078431372549" /> <Point X="1556.0" Y="1599.0" GraphRef="d8d81" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623365" /> </Interaction> <Interaction GraphId="df468"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="905.0" Y="898.0" GraphRef="c424d" RelX="-0.011494252873563218" RelY="1.0" /> <Point X="1040.0" Y="1809.0" GraphRef="a568f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618407" /> </Interaction> <Interaction GraphId="df712"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1599.0" Y="2308.0" GraphRef="fdd3d" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1608.0" Y="2285.0" GraphRef="f0024" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608048" /> </Interaction> <Interaction GraphId="e0557"> <Comment Source="Reactome">The endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EEPD1 was found to localize to the plasma membrane owing to the presence of a myristoylation site in its N terminus (Nelson JK et al. 2017). EEPD1 was identified as a direct transcriptional target of the sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and β (LXRβ, NR1H2) in murine bone marrow-derived macrophages and J774 macrophages and in human monocyte-like THP-1 cells (Nelson JK et al. 2017). Induction of EEPD1 by LXRs is tissue-specific and does not occur in HepG2 (liver) or C2C12 (muscle) cells (Nelson JK et al. 2017). Silencing expression of EEPD1 attenuated NR1H2,3 (LXRs)-stimulated apolipoprotein A-I (Apo A1)-dependent cholesterol efflux in THP1 and J774 cells (Nelson JK et al. 2017). Further, the level of cellular ATP-binding cassette transporter (ABCA1) content at the plasma membrane was reduced by 50% in both EEPD1-silenced macrophage cell lines (Nelson JK et al. 2017). ABCA1 is known to mediate the efflux of cellular cholesterol to lipid-free ApoA-I and thus initiates the biogenesis of high-density lipoprotein (HDL) (Reviewed in Phillips M.C. 2018). EEPD1 is thought to promote NR1H2,3-mediated cellular cholesterol efflux in macrophages post-transcriptionally by controlling cellular levels and activity of ABCA1 at the plasma membrane (Nelson JK et al. 2017). </Comment> <BiopaxRef>a96</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1573.0" Y="1746.0" /> <Point X="2025.0" Y="1747.0" /> <Anchor Position="0.0" Shape="None" GraphId="f07b7" /> <Anchor Position="0.99" Shape="None" GraphId="fc2de" /> <Anchor Position="0.5" Shape="None" GraphId="befc4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035180" /> </Interaction> <Interaction GraphId="e0a7a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1048.0" Y="1882.0" GraphRef="b36ad" RelX="0.849999999999909" RelY="0.009999999999990905" /> <Point X="1051.0" Y="1883.0" GraphRef="d6138" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="e0b78"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1779.0" Y="286.0" GraphRef="b79bf" RelX="0.9759036144578314" RelY="0.0" /> <Point X="1786.0" Y="323.0" GraphRef="d7da2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618486" /> </Interaction> <Interaction GraphId="e0dec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2025.0" Y="1747.0" GraphRef="fc2de" RelX="4.519999999999982" RelY="0.009999999999990905" /> <Point X="2028.0" Y="1747.0" GraphRef="b5b0c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035180" /> </Interaction> <Interaction GraphId="e0e7f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1563.0" Y="465.0" GraphRef="bf65e" RelX="0.9672131147540983" RelY="-0.0196078431372549" /> <Point X="1573.0" Y="442.0" GraphRef="d48c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605057" /> </Interaction> <Interaction GraphId="e0ebe"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1264.0" Y="550.0" GraphRef="df991" RelX="0.7400000000000091" RelY="-0.009999999999990905" /> <Point X="1267.0" Y="549.0" GraphRef="f0e60" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="e1030"> <Comment Source="Reactome">The gene expression of liver X receptor alpha (LXRα or NR1H3) is autoinduced in a tissue-specific manner ((Whitney KD et al. 2001; Laffitte BA et al. 2001; Li Y et al. 2002). In contrast, NR1H2 (LXRβ) expression is not autoregulated. NR1H3 (LXRα) induction was observed in multiple human cell types including monocyte-derived macrophages, the TPH-1 macrophage cell line and skin fibroblasts in response to NR1H3 and NR1H2 ligands (20(S)-hydroxycholesterol, 22(R)-hydroxycholesterol, 24(S),25-epoxycholesterol, GW3965 or T0901317) (Whitney KD et al. 2001; Laffitte BA et al. 2001; Li Y et al. 2002). No autoregulatory induction of NR1H3 was observed in mouse macrophages (Whitney KD et al. 2001; Laffitte BA et al. 2001; Li Y et al. 2002). There are conflicting data in the literature as to whether this autoregulatory loop is present (Lafitte BA et al. 2001; Li Y et al. 2002) or absent (Whitney DK et al. 2001) in human adipocytes and hepatocytes. T0901317 treatment up-regulated the gene expression of NR1H3 in a dose- and time-dependent fashion in differentiated human THP-1 cells (Li Y et al. 2002). Analysis of the human NR1H3 promoter revealed three LXR response elements (LXREs) (Laffitte BA et al. 2001; Li Y et al. 2002). One exhibited strong affinity for both NR1H2:RXR and NR1H3:RXR (Li Y et al. 2002). Deletions or mutations of this LXRE led to a dramatic loss in the ability of the promoter to respond to T0901317 in transient transfection assays in human hepatocarcinoma Huh-7 cells (Li Y et al. 2002). The other two LXREs are identical to each other, were found within highly conserved Alu repeats, and exhibited selective binding to NR1H3:RXR. In transfections, the first LXRE acted as a strong mediator of both NR1H3 (LXRα) and NR1H2 (LXRβ) activity, whereas the second LXRE acted as a weaker and selective mediator of NR1H3 (LXRα) activity (Li Y et al. 2002).</Comment> <BiopaxRef>daa</BiopaxRef> <BiopaxRef>b59</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1259.0" Y="1113.0" /> <Point X="1315.0" Y="1113.0" /> <Anchor Position="0.0" Shape="None" GraphId="cdec9" /> <Anchor Position="0.99" Shape="None" GraphId="c66ed" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035185" /> </Interaction> <Interaction GraphId="e2819"> <Comment Source="Reactome">ATP-binding cassette transporter A1 (ABCA1) is a target of micro RNA 33 (miR-33) (Rayner KJ et al. 2010; Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010; Zaiou M et al. 2018). The miR33 family consists of two intronic miRNAs, miR-33a and miR-33b, which are encoded within the introns of the sterol regulatory element-binding proteins (SREBP) 2 and 1 genes, respectively (Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010). Under conditions that stimulate SREBP transcription, miR-33a/b are co-expressed with their host genes and reciprocally regulate genes such as ABCA1 that are involved in cellular cholesterol efflux and high-density lipoprotein (HDL) biogenesis (Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010). Expression of the ABCA1 gene is induced by oxysterol-activated transcription factors liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) and their heterodimeric partners, retinoid X receptors (RXR) via functional LXR response element (LXRE) in target genes (Costet P et al. 2000; Ignatova ID et al. 2013). miR-33 was found to suppress expression of ABCA1 in human macrophages (THP-1) and hepatocytes (HepG2, Hep3B ) treated with a synthetic agonist, T0901317, of LXRs (Rayner KJ et al. 2010; Marquart TJ et al. 2010). Inhibition of endogenous miR-33 by anti-miR-33 increased the expression of ABCA1 in THP-1 and HepG2 cells (Rayner KJ et al. 2010). In vivo studies showed that liver ABCA1 protein and serum HDL-C levels were higher in miR-33-deficient mice than in control mice (Horie T et al. 2010). In line with this, a study reported that healthy individuals with high HDL-C levels often overexpress ABCA1 and ABCG1 and show a decrease of miR-33a in their peripheral blood mononuclear cells (Scherrer DZ et al. 2015). Analysis of the 3' untranslated region (3'UTR) of ABCA1 identified sequences that are partially complementary to miR-33 sequences (Marquart TJ et al. 2010). Importantly, these sequences are evolutionarily conserved across animal species (Marquart TJ et al. 2010). Further, a 3'UTR luciferase reporter assay showed that miR-33 directly binds the ABCA1 3′UTR when human embryonic kidney (HEK293T) cells were cotransfected with luciferase reporter constructs fused to the 3′UTR of ABCA1 and control miR or miR-33 (Rayner KJ et al. 2010; Horie T et al. 2010; Najafi-Shoushtari SH et al. 2010). Mutation in the potential binding site in the 3′-UTR abolished the effect of miR-33 (Horie T et al. 2010). The Reactome event describes the miR-33- regulated translation of ABCA1 mRNA in response to NR1H2,3 natural ligands. The annotation is based on studies with T0901317, the synthetic agonist of NR1H2,3 (Rayner KJ et al. 2010; Marquart TJ et al. 2010).</Comment> <BiopaxRef>d90</BiopaxRef> <BiopaxRef>a32</BiopaxRef> <BiopaxRef>eaf</BiopaxRef> <BiopaxRef>f0f</BiopaxRef> <BiopaxRef>c56</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1766.0" Y="363.0" /> <Point X="1817.0" Y="364.0" /> <Anchor Position="0.0" Shape="None" GraphId="ec5ab" /> <Anchor Position="0.99" Shape="None" GraphId="ae1c6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624925" /> </Interaction> <Interaction GraphId="e2c45"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2101.0" Y="1247.0" GraphRef="c789c" RelX="5.630000000000109" RelY="0.01999999999998181" /> <Point X="2104.0" Y="1247.0" GraphRef="f26dd" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031512" /> </Interaction> <Interaction GraphId="e2e57"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1266.0" Y="660.0" GraphRef="af0ed" RelX="0.75" RelY="0.009999999999990905" /> <Point X="1269.0" Y="660.0" GraphRef="e4796" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029521" /> </Interaction> <Interaction GraphId="e3038"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1456.0" Y="1268.0" GraphRef="cc028" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1253.0" Y="1210.0" GraphRef="ab3dc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031522" /> </Interaction> <Interaction GraphId="e320c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1094.0" Y="2172.0" GraphRef="ababf" RelX="1.0" RelY="0.0" /> <Point X="1642.0" Y="2200.0" GraphRef="cf071" RelX="-28.0" RelY="0.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605051" /> </Interaction> <Interaction GraphId="e4729"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="967.0" Y="2172.0" GraphRef="f7a9b" RelX="1.2200000000000273" RelY="-0.01999999999998181" /> <Point X="970.0" Y="2172.0" GraphRef="ababf" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="e4aa1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1267.0" Y="1629.0" GraphRef="b0282" RelX="1.7899999999999636" RelY="0.01999999999998181" /> <Point X="1270.0" Y="1631.0" GraphRef="d5581" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657786" /> </Interaction> <Interaction GraphId="e4e80"> <Comment Source="Reactome">The ileal bile acid-binding protein (I-BABP, also known as FABP6) is encoded by FABP6 gene. FABP6 is a 14 kDa cytosolic protein which binds bile acids with a high affinity. FABP6 gene expression was directly up-regulated by liver X-receptor α (LXRα or NR1H3) and LXRβ (NR1H2) in human enterocyte-like Caco-2 cells when the cells were transiently cotransfected with a FABP6 promoter fragment cloned upstream of the CAT reporter gene and expression vectors for NR1H3 or NR1H2 and retinoid X receptor α (RXRα) (Landrier JF et al. 2003). Electrophoretic mobility shift assays demonstrated that the NR1H3:RXR heterodimer specifically recognized a farnesoid Xâ€�receptorâ€�responsive element (FXRE) which functioned as an LXR responsive element (LXRE) in the promoter of FABP6 gene (Landrier JF et al. 2003). Similar data have been reported for the PLTP gene suggesting that the FXRE sequence can function as an LXRâ€�binding site in different genes (Mak PA et al. 2002). Besides, FABP6 gene expression can be indirectly up-regulated by cholesterol through the activation of sterol-responsive element-binding protein 1c (SREBP1c) by liver X-receptors (Zaghini I et al. 2002).</Comment> <BiopaxRef>ced</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1602.0" Y="2359.0" /> <Point X="1712.0" Y="2386.0" /> <Anchor Position="0.0" Shape="None" GraphId="cb097" /> <Anchor Position="0.99" Shape="None" GraphId="dadae" /> <Anchor Position="0.5" Shape="None" GraphId="cb53c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9607342" /> </Interaction> <Interaction GraphId="e4fa9"> <Comment Source="Reactome">The sterol regulatory element-binding protein 1 (SREBP1) is encoded by the SREBF1 gene. SREBF1 is transcribed to yield mRNA and the mRNA is translated to yield protein. The SREBF1 gene can produce two proteins, SREBP1a and SREBP1c, by use of different promoters (Hua X et al. 1995) and unique first exons (Shimomura I et al. 1997). In humans and mice, the SREBP1c is the predominant SREBF1 isoform in the liver that regulates fatty acid (FA) metabolism (Shimomura I et al. 1997; Sato R 2010; Horton JD et al. 2002). The oxysterol receptors liver X receptor alpha (LXRα, NR1H3) and LXRβ (NR1H2) were reported to mediate hepatic lipogenesis in rodents and humans by direct binding and upregulation of SREBF1 (SREBP1c) which controls the transcription of genes involved in FA biosynthesis (Schultz JR et al. 2000; Repa JJ et al. 2000; Yoshikawa T et al. 2001). NR1H2 &amp; NR1H3 were shown to activate the mouse SREBF1 (SREBP1c) promoter (Yoshikawa T et al. 2001). In cell transfection studies using human embryonic kidney 293 (HEK293) cells, expression of either NR1H2 or NR1H3 activated the SREBF1 promoter-luciferase reporter gene in a dose-dependent manner (Yoshikawa T et al. 2001). Deletion and mutation studies, as well as gel mobility shift assays, identified two LXR response elements (LXRE) in the SREBF1c promoter region that regulate expression of SREBP1c by both LXR and RXR agonists (Repa JJ et al. 2000; Yoshikawa T et al. 2001). In mice receiving oral cholesterol, T0901317 (LXR agonist) or LG268 (RXR agonist), SREBP1c mRNA levels were elevated in nearly all tissues tested (Repa JJ et al. 2000). In human hepatoma HepG2 cells, SREBP1 mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR:RXR activation can induce endogenous SREBP1 expression (Yoshikawa T et al. 2001). The activation of SREBF1 by NR1H2 or NR1H3 is associated with an increase in nuclear SREBP1c protein, resulting in the activation of many genes involved in lipogenesis, such as fatty acid synthase (FASN) gene, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase 1 (SCD1) (Yoshikawa T et al. 2001; Chen G et al. 2004). However, NR1H2, NR1H3 may activate lipogenic gene transcription directly by binding LXRE found in the promoter regions of several genes, such as FASN ( or FAS), ACCα and SCD1 (Yoshikawa T et al. 2001; Joseph SB et al. 2002; Chu K et al. 2006; Talukdar S &amp; Hillgartner FB 2006). Mice carrying a targeted disruption in the NR1H3 (LXRα) gene were deficient in expression of FAS, SCD1, and SREBP1 (Peet DJ et al. 1998). These data demonstrate that LXR:RXR can modify the expression of genes for lipogenic enzymes directly or by regulating SREBP1c expression. Liang and colleagues genetically deleted only the SREBF-1c isoform from mice and provided these animals with the LXR agonist T0901317. These knockout mice continued to exhibit enhanced hepatic lipogenesis, albeit only about 40% that observed in ligand-treated wildtype mice, suggesting that SREBP1c is responsible for over half of LXR-associated lipogenic capacity (Liang G et al. 2002).&lt;br&gt;</Comment> <BiopaxRef>bca</BiopaxRef> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1587.0" Y="2114.0" /> <Point X="1818.0" Y="2113.0" /> <Anchor Position="0.0" Shape="None" GraphId="c88e1" /> <Anchor Position="0.99" Shape="None" GraphId="e5093" /> <Anchor Position="0.5" Shape="None" GraphId="b1469" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605056" /> </Interaction> <Interaction GraphId="e5018"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="567.0" Y="2496.0" GraphRef="e04a8" RelX="0.5199999999999818" RelY="0.0" /> <Point X="570.0" Y="2453.0" GraphRef="e3a94" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029566" /> </Interaction> <Interaction GraphId="e5586"> <Comment Source="Reactome">Phospholipid transfer protein (PLTP) gene expression can be transcriptionally activated by liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) that belong to the nuclear receptor superfamily (Mak PA et al. 2002; Cao G et al. 2002; Laffitte BA et al. 2003). NR1H2 and NR1H3 act as cellular sensors of sterol levels and are transcriptionally activated by oxidized forms of cholesterol, oxysterols (Janowski BA et al. 1996). Synthetic LXR agonists, T0901317 or GW3965, induced the expression of PLTP in various tissues of mice in a coordinate manner with known LXR target genes (Cao G et al. 2002; Laffitte BA et al. 2003). PLTP expression was also highly induced by LXR (NR1H2 and NR1H3) and retinoid X receptor (RXR) agonists in murine peritoneal and human THP-1 macrophages (Mak PA et al. 2002; Laffitte BA et al. 2003). The ability of synthetic and oxysterol ligands to regulate PLTP mRNA in macrophages and liver was lost in animals lacking both NR1H3 (LXRα) and NR1H2 (LXRβ), confirming the critical role of these receptors (Laffitte BA et al. 2003). Once activated, NR1H2 or 3 recognize an LXR response element (LXRE) sequence containing a variant direct-repeat-4 (DR4) motif in the promoter regions of target genes. The PLTP promoter contains a high-affinity LXRE that was found to bind NR1H3:RXR heterodimers in vitro, and was activated by NR1H3:RXR in transient-transfection studies (Mak PA et al. 2002; Laffitte BA et al. 2003). &lt;p&gt;In addition to NR1H2 or NR1H3, PLTP expression is regulated by other nuclear receptor RXR heterodimers, including peroxisome proliferator-activated receptor α (PPARα):RXR and farnesoid X receptor (FXR):RXR (Mak PA et al. 2002; Tu AY &amp; Albers JJ 2001).</Comment> <BiopaxRef>b4c</BiopaxRef> <BiopaxRef>c65</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1205.0" Y="959.0" /> <Point X="1269.0" Y="960.0" /> <Anchor Position="0.0" Shape="None" GraphId="acd9e" /> <Anchor Position="0.99" Shape="None" GraphId="ae736" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624353" /> </Interaction> <Interaction GraphId="e57fa"> <Comment Source="Reactome">The perilipin 1 (PLIN1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Liver X receptors (LXRα, NR1H2,3) up-regulate basal human adipocyte lipolysis partially through NR1H2,3 binding to the PLIN1 promoter and down-regulation of PLIN1 expression (Stenson BM et al. 2011). By selective knockdown of either NR1H2 or NR1H3, NR1H3 was found to be the major isoform mediating the lipolysis-related effects of NR1H2,3. The Reactome event of NR1H2,3-regulated expression of PLIN1 is inferred from the analogous event regulated by a synthetic NR1H2,3 agonist GW3965 (Stenson BM et al. 2011).</Comment> <BiopaxRef>d9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1608.0" Y="2285.0" /> <Point X="1703.0" Y="2311.0" /> <Anchor Position="0.0" Shape="None" GraphId="f0024" /> <Anchor Position="0.99" Shape="None" GraphId="f73d2" /> <Anchor Position="0.5" Shape="None" GraphId="e5116" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9608048" /> </Interaction> <Interaction GraphId="e6a30"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1817.0" Y="364.0" GraphRef="ae1c6" RelX="0.5099999999999909" RelY="0.009999999999990905" /> <Point X="1820.0" Y="365.0" GraphRef="b70f2" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624925" /> </Interaction> <Interaction GraphId="e801a"> <Comment Source="Reactome">The apolipoprotein D (APOD) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. APOD is an atypical apolipoprotein that belongs to the lipocalin family, and is expressed by a wide variety of cells and tissues (Drayna D et al. 1986). The liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) were found to regulate the expression of the APOD gene in cultured cells and in vivo (Hummasti S et al. 2004; Lai C-J et al. 2017). Synthetic LXR agonist treatment of mouse adipocytes (3T3-L1 cells) and human umbilical vein endothelial cells (HUVECs) resulted in increased mRNA and protein levels of APOD (Hummasti S et al. 2004; Lai C-J et al. 2017). An LXR response element (LXRE) was identified in the human APOD gene promoter, and binding of LXRα (NR1H3):RXRa heterodimers was demonstrated by electrophoretic mobility shift assay (EMSA) and luciferase cell reporter assay (Hummasti S et al. 2004). Mice treated with synthetic LXR agonists exhibited increased APOD mRNA levels in adipose tissue, skeletal muscle and cerebellum, but not liver (Hummasti S et al. 2004; Repa JJ et al. 2007). In humans, APOD is found in the plamsa, associated with high-density lipoprotein (HDL), and polymorphisms have been linked to metabolic disease. APOD has also been suggested to be neuroprotective (Pascua-Maestro R et al 2019).</Comment> <BiopaxRef>d10</BiopaxRef> <BiopaxRef>b5e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1586.0" Y="1661.0" /> <Point X="2086.0" Y="1657.0" /> <Anchor Position="0.0" Shape="None" GraphId="ea77e" /> <Anchor Position="0.99" Shape="None" GraphId="f2d9d" /> <Anchor Position="0.5" Shape="None" GraphId="a213d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657767" /> </Interaction> <Interaction GraphId="e8282"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="550.0" Y="2049.0" GraphRef="e102d" RelX="0.9534883720930233" RelY="0.0" /> <Point X="963.0" Y="1881.0" GraphRef="ab3d7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028533" /> </Interaction> <Interaction GraphId="e8432"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2086.0" Y="1342.0" GraphRef="f5e5f" RelX="5.329999999999927" RelY="-0.07999999999992724" /> <Point X="2089.0" Y="1342.0" GraphRef="ab38f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031510" /> </Interaction> <Interaction GraphId="e8e97"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1179.0" Y="869.0" GraphRef="aa453" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035133" /> </Interaction> <Interaction GraphId="e9624"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1115.0" Y="1564.0" GraphRef="caf5d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623366" /> </Interaction> <Interaction GraphId="e9636"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1566.0" Y="724.0" GraphRef="b6012" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1575.0" Y="701.0" GraphRef="b279c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029531" /> </Interaction> <Interaction GraphId="e986d"> <Comment Source="Reactome">The apolipoprotein E (APOE) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. APOE, a 34-kD glycoprotein, is involved in lipoprotein clearance by serving as a ligand for the low-density lipoprotein (LDL) receptor family. APOE is primarily lipidated via the ATP-binding cassette transporter 1 (ABCA1), and both are under transcriptional regulation by the liver X receptor α (LXRα or NR1H3) and LXRβ (NR1H2) whose natural ligands are oxysterols such as 24(S),25-epoxycholesterol (24(S),25-epoxy) (Laffitte BA et al. 2001; Beyea MM et al. 2007). The endogenous and synthetic agonists of NR1H2 or NR1H3 increased expression of APOE in human and murine macrophages, and murine adipocytes but not in liver (Laffitte BA et al. 2001; Mak PA et al 2002; Beyea MM et al. 2006). This tissue-specific regulation is conferred by the presence of LXR response elements (LXREs) in multienhancer regions ME.1 and ME.2 downstream of the APOE gene that are revealed only in adipose tissue and macrophages (Shih SJ et al. 2000). In addition, ligand-activated NR1H2 and NR1H3 lead to a dramatic increase in APOE mRNA and protein expression as well as secretion of APOE in a human astrocytoma cell line (CCF-STTG1 cells) to impact cholesterol efflux (Liang Y et al. 2004; Abildayeva K et al. 2006). In the central nervous system, APOE is considered a major apoprotein acceptor for the efflux of cholesterol in the formation of high-density lipoprotein (HDL)-like particles necessary for intercellular lipid trafficking, and is implicated in various neurodegenerative diseases, such as Alzheimer’s (reviewed in Hirsch-Reinshagen V &amp; Wellington CL 2007).</Comment> <BiopaxRef>a35</BiopaxRef> <BiopaxRef>d78</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1538.0" Y="1245.0" /> <Point X="2101.0" Y="1247.0" /> <Anchor Position="0.0" Shape="None" GraphId="f6a37" /> <Anchor Position="0.99" Shape="None" GraphId="c789c" /> <Anchor Position="0.5" Shape="None" GraphId="dd058" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031512" /> </Interaction> <Interaction GraphId="eb3f7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1190.0" Y="551.0" GraphRef="bdca9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="ebec4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1870.0" Y="322.0" GraphRef="adbe7" RelX="0.8399999999999181" RelY="-0.009999999999990905" /> <Point X="1873.0" Y="323.0" GraphRef="c3e9f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618486" /> </Interaction> <Interaction GraphId="ec1fc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1579.0" Y="616.0" GraphRef="baf9c" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1588.0" Y="593.0" GraphRef="a6170" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024361" /> </Interaction> <Interaction GraphId="ec42a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1229.0" Y="1487.0" GraphRef="a93e7" RelX="0.5799999999999272" RelY="-0.01999999999998181" /> <Point X="1232.0" Y="1487.0" GraphRef="f3054" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035143" /> </Interaction> <Interaction GraphId="ed87e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1898.0" Y="272.0" GraphRef="be9a7" RelX="0.8199999999999363" RelY="0.0" /> <Point X="1901.0" Y="272.0" GraphRef="e9c14" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657791" /> </Interaction> <Interaction GraphId="edbdc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1095.0" Y="2079.0" GraphRef="d7f48" RelX="0.9844961240310077" RelY="0.0" /> <Point X="1654.0" Y="2114.0" GraphRef="b1469" RelX="-48.5" RelY="0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605056" /> </Interaction> <Interaction GraphId="ede35"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1248.0" Y="1707.0" GraphRef="a6c2d" RelX="1.0" RelY="0.0" /> <Point X="1629.0" Y="1748.0" GraphRef="befc4" RelX="-170.0" RelY="1.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035180" /> </Interaction> <Interaction GraphId="ee460"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1600.0" Y="2520.0" GraphRef="f519b" RelX="0.978021978021978" RelY="-0.0196078431372549" /> <Point X="1610.0" Y="2497.0" GraphRef="e91c4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029536" /> </Interaction> <Interaction GraphId="ee740"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1190.0" Y="551.0" GraphRef="bdca9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="ee86b"> <Comment Source="Reactome">Stearoyl-CoA desaturase (SCD) is an enzyme required for the biosynthesis of oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides and cholesterol esters (Bene H et al. 2001; Paton CM &amp; Ntambi JM 2009). Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are the oxysterol receptors that were shown to regulate the expression of SCD gene in mouse liver, mouse J774 macrophages cells, human hepatoma HuH7 and human arterial endothelial cells (HAEC) (Wang Y et al. 2004; Chu K et al. 2006; Herzog B et al. 2007; Peter A et al. 2008). The evidence for the Reactome event of NR1H2,3- mediated SCD activity comes mostly from the studies with the synthetic NR1H2,3 agonist T0901317 (Chu K et al. 2006; Peter A et al. 2008). Serial deletion and point mutation analyses in reporter gene assays identified an NR1H2,3 (LXR) response element in the mouse SCD1 promoter (Chu K et al. 2006). Further, a gel mobility shift assay showed the binding of NR1H3 (LXRα):RXRA heterodimer to the LXRE-DR4 element in the promoter region of the mouse SCD1 gene (Chu K et al. 2006). The human SCD promoter structure is very similar to that of the mouse SCD1 isoform and contains conserved regulatory sequences for the binding of several transcription factors (Bene H et al. 2001). Analysis of hepatic lipogenic gene expression indicated that nuclear receptor-interacting protein 140 (RIP140 or NRIP1) was required for NR1H3 to be able to stimulate the expression of the SCD gene in WT and NRIP1 null mice after administration of T0901317 (Herzog B et al. 2007). These findings are supported by the failure of T0901317 to stimulate the expression of SCD gene in cultured human hepatoma HuH7 cells depleted of NRIP1 by siNRIP1 (Herzog B et al. 2007). Further, chromatin immunoprecipitation (ChIP) assays using HuH7 cells treated with T0901317 showed that both NR1H3 (LXRα) and NRIP1 bind directly to promoters in the vicinity of the LXRE of the NR1H2,3 target genes FAS, SREBP1c and NR1H3 (Herzog B et al. 2007). Thus, NRIP1 functions as a coactivator of NR1H2,3 and is required to stimulate expression of genes involved in lipogenesis including SCD gene. However, the function of NRIP1 as a cofactor for NR1H2,3 in liver varies according to the target genes and metabolic process, serving as a coactivator in lipogenesis but as a corepressor in gluconeogenesis (Herzog B et al. 2007). Studies performed with T0901317 in wildtype vs. NR1H3-/- (LXRα-/-) and NR1H2 (LXRβ -/-) mice suggest that SCD1 is primarily regulated by NR1H3 (Zhang X et al. 2014).</Comment> <BiopaxRef>fad</BiopaxRef> <BiopaxRef>b38</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="924.0" Y="1970.0" /> <Point X="991.0" Y="1969.0" /> <Anchor Position="0.0" Shape="None" GraphId="db076" /> <Anchor Position="0.99" Shape="None" GraphId="d5e29" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028526" /> </Interaction> <Interaction GraphId="eea59"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2046.0" Y="453.0" GraphRef="eefb2" RelX="0.0" RelY="1.0" /> <Point X="2032.0" Y="490.0" GraphRef="b2154" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9619756" /> </Interaction> <Interaction GraphId="ef5c1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="603.0" Y="332.0" GraphRef="f506a" RelX="1.0" RelY="0.0" /> <Point X="619.0" Y="403.0" GraphRef="c3823" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024326" /> </Interaction> <Interaction GraphId="ef8e8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1923.0" Y="1824.0" GraphRef="fec70" RelX="0.7999999999999545" RelY="0.009999999999990905" /> <Point X="1926.0" Y="1825.0" GraphRef="cb55b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618405" /> </Interaction> <Interaction GraphId="f0cd1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1543.0" Y="1373.0" GraphRef="c5f19" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="1553.0" Y="1350.0" GraphRef="f293b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031510" /> </Interaction> <Interaction GraphId="f2cc5"> <Comment Source="Reactome">The ATP binding cassette transporter G1 (ABCG1, formerly called “whiteâ€� and/or ABC8) exhibits a tissue-specific expression pattern with high expression levels found in macrophage/microglia, lung, brain, spleen, adrenal gland, heart and liver (Croop JM et al 1997; Klucken J et al. 2000). The ABCG1 gene is transcriptionally activated by cholesterol-loading and agonists of liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) and retinoid X receptors (RXRs) and has been implicated in the efflux of cholesterol to high density lipoprotein (HDL) (Venkateswaran A et al. 2000; Kennedy MA et al. 2001; Ayaori M et al. 2012; Sabol SL et al. 2005; Jakobsson T et al. 2009). Beyond a role in cellular lipid homeostasis, ABCG1 participates in glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase (Olivier M et al. 2012; Sturek JM et al. 2010; Hardy LM et al. 2017). ABCG1 gene has been mapped to chromosome 21q22.3 and multiple human ABCG1 transcripts have been detected resulting from different transcription initiation and alternative mRNA splicing (Croop JM et al 1997; Langmann T et al. 2000; Lorkowski S et al. 2001; Kennedy MA et al. 2001). Although discrepancies were initially found among reports in the literature regarding the structure of the ABCG1 gene, it is now established that the ABCG1 gene is composed of 23 exons encoding a protein that forms a half transporter with 6 transmembrane spanning domains and a single intracellular nucleotide binding domain (NBD) (Langmann T et al. 2000; Kennedy MA et al. 2001; Hardy LM et al. 2017). This NBD domain contains highly conserved Walker A and Walker B motifs and is required for the binding and the hydrolysis of ATP which might provide required energy to transport substrates across the membrane (Cserepes J et al. 2004; Hirayama H et al. 2013; Vaughan AM &amp; Oram JF 2005). Induction of ABCG1 expression by LXR agonists likely involves the presence of multiple LXR response elements (LXRE) throughout the ABCG1 gene (Kennedy MA et al. 2001; Sabol SL et al. 2005; Uehara Y et al. 2007). Electromobility shift assays demonstrated that NR1H3 and RXR alpha bind to two LXREs in intron 7 (Kennedy MA et al. 2001). Another set of two functional LXREs, LXRE-A and LXRE-B, was identified in the first and second introns of the human ABCG1 gene (Sabol SL et al. 2005). Further, studies of the transcriptional activity of truncated human ABCG1 promoter constructs showed that the NR1H2,3:RXR response region (or LXRE) is located in the human ABCG1 promoter A (LXRE-A) between -303 and -233 (Uehara Y et al. 2007).&lt;p&gt;G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2,3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009). In macrophages, silencing of GPS2 by RNA interference reduced ABCG1 expression and diminished ABCG1-mediated cholesterol efflux. Chromatin immunoprecipitation analysis and 2-hybrid and protein-protein interaction assays revealed that GPS2 interacted with NR1H2,3:RXR heterodimer at the LXRE of the ABCG1 promoter (Jakobsson T et al. 2009). Chromosome conformation capture assays using the human hepatoma cell line, Huh7, transfected with GPS2-targeting siRNAs showed that GPS2 was required for intrachromosomal communication of the ABCG1 promoter and enhancer triggered by NR1H2,3 activation (Jakobsson T et al. 2009). Further, ligand activation of NR1H2,3 induced two functionally coupled GPS2-dependent processes: (1) receptor recruitment to an ABCG1 promoter/enhancer unit and (2) lysine-specific histone demethylase 1 (KDM1)-dependent H3K9 demethylation (Jakobsson T et al. 2009). The model suggests that the H3K9 methylation imposes a chromatin barrier at certain genomic loci (e.g., ABCG1) that prevents nuclear receptors (NR) (e.g., NR1H2,3) from high-affinity DNA binding (as detected by ChIP assays). Ligand activation in vivo triggers recruitment of KDMs to NRs (in the case of NR1H2,3 via GPS2), thereby facilitating H3K9 demethylation and high-affinity DNA binding (Jakobsson T et al. 2009).</Comment> <BiopaxRef>eaa</BiopaxRef> <BiopaxRef>bb6</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1190.0" Y="551.0" /> <Point X="1264.0" Y="550.0" /> <Anchor Position="0.0" Shape="None" GraphId="bdca9" /> <Anchor Position="0.99" Shape="None" GraphId="df991" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="f4bab"> <Comment Source="Reactome">Endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) was identiified as a direct transcriptional target of liver X receptors (LXR alpha (NR1H3) and LXR beta (NR1H2)) in murine bone marrow-derived macrophages (BMDM), J774 macrophages and in human monocyte-like THP-1 cells (Nelson JK et al. 2017). An LXR alpha (NR1H3) ChIP-seq study identified a LXR-response element (LXRE) in intron 2 of EEPD1 gene (Nelson JK et al. 2017; Feldmann R et al. 2013).</Comment> <BiopaxRef>a96</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1063.0" Y="1707.0" /> <Point X="1113.0" Y="1707.0" /> <Anchor Position="0.0" Shape="None" GraphId="c4a56" /> <Anchor Position="0.99" Shape="None" GraphId="b0248" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9035167" /> </Interaction> <Interaction GraphId="f4e00"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1275.0" Y="1403.0" GraphRef="bbfee" RelX="0.6099999999999" RelY="0.0" /> <Point X="1278.0" Y="1403.0" GraphRef="e87b3" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031521" /> </Interaction> <Interaction GraphId="f5fa5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1401.0" Y="660.0" GraphRef="e4796" RelX="1.0" RelY="0.0" /> <Point X="1624.0" Y="702.0" GraphRef="daeb8" RelX="-171.0" RelY="0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029531" /> </Interaction> <Interaction GraphId="f6507"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1117.0" Y="604.0" GraphRef="ef8f1" RelX="0.9487179487179487" RelY="0.0" /> <Point X="1190.0" Y="551.0" GraphRef="bdca9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024386" /> </Interaction> <Interaction GraphId="f6a22"> <Comment Source="Reactome">Activation by synthetic ligands of liver X receptor (LXR) α (NR1H3) led to the suppression of gluconeogenesis in mouse hepatocytes by down-regulation of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK) gene (Laffitte BA et al. 2003; Herzog B et al. 2007). Notably, both NR1H3 and NR1H2 have been shown to co-localize and interact with receptor-interacting protein 1 (NRIP1 or RIP140) (Jakobsson T et al. 2007; Herzog B et al. 2007). Indeed, depending on the gene, RIP140 can function both as a co-activator and co-repressor of NR1H2 or NR1H3. In the liver for instance, NRIP1 may activate NR1H3 (LXRα)-mediated transcription from lipogenic genes such as FASN and repress transcription of PCK1 gene to regulate metabolic pathways (Herzog B et al. 2007). </Comment> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="845.0" Y="2174.0" /> <Point X="967.0" Y="2172.0" /> <Anchor Position="0.0" Shape="None" GraphId="bc8b3" /> <Anchor Position="0.99" Shape="None" GraphId="f7a9b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9028524" /> </Interaction> <Interaction GraphId="f6f0b"> <Comment Source="Reactome">Angiopoietin-Like 3 (ANGPTL3) is a direct target gene of the LXR:RXR heterodimer. Synthetic and endogenous oxysterol ligand administration to human HepG2 cells or mice results in increased mRNA and protein levels of ANGPTL3 (Kaplan R et al. 2003). An LXR response element (LXRE) was identified in the promoter of human ANGPTL3 which conferred ligand and receptor-specific regulation in luciferase cell reporter assays (Kaplan R et al. 2003). ANGPTL3 is a secreted protein that inhibits activity of lipoprotein lipase and endothelial lipase (Shimizugawa T et al. 2002), and the LXR-mediated upregulation of this gene&#xD; likely contributes (along with hepatic lipogenesis) to the severe hypertriglyceridemia associated with use of LXR drugs (Inaba T et al. 2003)</Comment> <BiopaxRef>de1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="662.0" Y="2389.0" /> <Point X="920.0" Y="2389.0" /> <Anchor Position="0.0" Shape="None" GraphId="e1c7e" /> <Anchor Position="0.99" Shape="None" GraphId="b6a8e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657836" /> </Interaction> <Interaction GraphId="f7e23"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1222.0" Y="1310.0" GraphRef="b06fb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031518" /> </Interaction> <Interaction GraphId="f8900"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1410.0" Y="1403.0" GraphRef="e87b3" RelX="1.0" RelY="0.0" /> <Point X="1605.0" Y="1444.0" GraphRef="a7675" RelX="-213.5" RelY="3.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031527" /> </Interaction> <Interaction GraphId="f8c4b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2077.0" Y="996.0" GraphRef="c17fe" RelX="4.9099999999998545" RelY="0.01999999999998181" /> <Point X="2083.0" Y="997.0" GraphRef="afd72" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624365" /> </Interaction> <Interaction GraphId="f9480"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1765.0" Y="329.0" GraphRef="e9e5b" RelX="1.0" RelY="0.0" /> <Point X="1766.0" Y="363.0" GraphRef="ec5ab" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624925" /> </Interaction> <Interaction GraphId="f9635"> <Comment Source="Reactome">The angiopoietin-Like 3 (ANGPTL3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. ANGPTL3 is a direct target gene of the LXR:RXR heterodimer. Synthetic and endogenous oxysterol ligand administration to human HepG2 cells or mice results in increased mRNA and protein levels of ANGPTL3 (Kaplan R et al. 2003). An LXR response element (LXRE) was identified in the promoter of human ANGPTL3 which conferred ligand and receptor-specific regulation in luciferase cell reporter assays (Kaplan R et al. 2003). ANGPTL3 is a secreted protein that inhibits activity of lipoprotein lipase and endothelial lipase (Shimizugawa T et al. 2002), and the LXR-mediated upregulation of this gene likely contributes (along with hepatic lipogenesis) to the severe hypertriglyceridemia associated with use of LXR drugs (Inaba T et al. 2003)</Comment> <BiopaxRef>de1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1605.0" Y="2419.0" /> <Point X="2083.0" Y="2418.0" /> <Anchor Position="0.0" Shape="None" GraphId="c923c" /> <Anchor Position="0.99" Shape="None" GraphId="fec09" /> <Anchor Position="0.5" Shape="None" GraphId="ea7b6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657775" /> </Interaction> <Interaction GraphId="fa519"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="948.0" Y="887.0" GraphRef="c424d" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1253.0" Y="1210.0" GraphRef="ab3dc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031522" /> </Interaction> <Interaction GraphId="fab60"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1839.0" Y="1824.0" GraphRef="a5faa" RelX="0.9834710743801653" RelY="0.0" /> <Point X="1843.0" Y="1823.0" GraphRef="b8c7b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618405" /> </Interaction> <Interaction GraphId="faf69"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1735.0" Y="1596.0" GraphRef="ea990" RelX="1.7899999999999636" RelY="-0.029999999999972715" /> <Point X="1738.0" Y="1596.0" GraphRef="df3fc" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623365" /> </Interaction> <Interaction GraphId="fb0ff"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1734.0" Y="1932.0" GraphRef="fc2ba" RelX="1.6199999999998909" RelY="0.009999999999990905" /> <Point X="1737.0" Y="1933.0" GraphRef="ea6e5" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9605063" /> </Interaction> <Interaction GraphId="fb4c0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1508.0" Y="1017.0" GraphRef="f8540" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1205.0" Y="959.0" GraphRef="acd9e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624353" /> </Interaction> <Interaction GraphId="fb9ec"> <Comment Source="Reactome">Ligand-activated liver X receptors (LXRα, NR1H3 and LXRβ NR1H2) induce expression of a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 in both human and mouse macrophages (Mak PA et al. 2002). Induction was attenuated or abolished in macrophages derived from LXR α/β-/- mice. Studies with reporter genes suggest that the LXR response element (LXRE) in the distal multienhancer regions ME.1 and ME.2 are necessary for the expression of this gene cluster (Mak PA et al. 2002). These secreted apolipoproteins regulate lipid transport and catabolism. In particular, APOC1 has been suggested to serve as an inhibitor of cholesteryl ester transfer protein (CETP) activity to impact cholesterol distribution among lipoprotein particles (Gautier T et al. 2000).</Comment> <BiopaxRef>db5</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1222.0" Y="1310.0" /> <Point X="1302.0" Y="1310.0" /> <Anchor Position="0.0" Shape="None" GraphId="b06fb" /> <Anchor Position="0.99" Shape="None" GraphId="d7f65" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031518" /> </Interaction> <Interaction GraphId="fc6b0"> <Comment Source="Reactome">Apolipoprotein E (APOE), a 34-kD glycoprotein, is involved in lipoprotein clearance by serving as a ligand for the low-density lipoprotein (LDL) receptor family. APOE is primarily lipidated via the ATP-binding cassette transporter A1 (ABCA1), and both are under transcriptional regulation by the liver X receptor α (LXRα or NR1H3) and LXRβ (NR1H2) (Laffitte BA et al. 2001; Beyea MM et al. 2007). The ligand-activated NR1H2 and NR1H3, whose natural ligands are oxysterols, function as obligate heterodimers with retinoid X receptor (RXR) to regulate the expression of target genes through binding to LXR response elements (LXREs) within the regulatory region of their target genes. Both NR1H2:RXRα and NR1H3 :RXRα heterodimers were reported to regulate APOE transcription directly through interaction with conserved LXREs found within tissue-specific enhancer regions (multienhancers ME.1 and ME.2) that confer APOE expression in adipose tissue and macrophages (Shih SJ et al. 2000; Laffitte BA et al. 2001). A low-affinity LXRE was also found in the promoter region of the APOE gene (Laffitte BA et al. 2001). Further, oxysterol-binding protein related protein 1S (ORP1S) was shown to associate with NR1H2 and NR1H3 in the nucleus (Lee S et al. 2012). ORP1S promoted the binding of the receptors to LXREs and specifically enhanced NR1H2,3-dependent transcription of APOE via the ME.1 and ME.2 of the APOE gene (Lee S et al. 2012).</Comment> <BiopaxRef>a35</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1253.0" Y="1210.0" /> <Point X="1285.0" Y="1209.0" /> <Anchor Position="0.0" Shape="None" GraphId="ab3dc" /> <Anchor Position="0.99" Shape="None" GraphId="a6aad" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9031522" /> </Interaction> <Interaction GraphId="fcdac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2035.0" Y="538.0" GraphRef="f0df7" RelX="0.029999999999972715" RelY="0.4800000000000182" /> <Point X="2039.0" Y="541.0" GraphRef="b8e35" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9619756" /> </Interaction> <Interaction GraphId="fe08a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1750.0" Y="423.0" GraphRef="f609b" RelX="-0.010101010101010102" RelY="-1.0" /> <Point X="1786.0" Y="323.0" GraphRef="d7da2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9618486" /> </Interaction> <Interaction GraphId="fe147"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="343.0" Y="781.0" GraphRef="d3573" RelX="0.9801980198019802" RelY="0.0" /> <Point X="1191.0" Y="659.0" GraphRef="b0f97" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9029521" /> </Interaction> <Interaction GraphId="fe8a6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="892.0" Y="400.0" GraphRef="b8f8c" RelX="0.6100000000000136" RelY="0.0" /> <Point X="931.0" Y="398.0" GraphRef="c8e1b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9024334" /> </Interaction> <Interaction GraphId="fe9e6"> <Comment Source="Reactome">The phospholipid transfer protein (PLTP) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PLTP is implicated in cholesterol and phospholipid transfer from triglyceride-rich lipoproteins to HDL during lipolysis by lipoprotein lipase, and in HDL remodeling (formation of β-HDL and large HDL) (Albers JJ et al. 2012; Jiang XC 2018). Beyond its impact on lipoprotein metabolism, PLTP has been reported to modulate inflammation and immune responses (Audo R et al. 2018). PLTP is expressed ubiquitously (Day JR et al. 1994). The highest expression levels in human tissues were observed in ovary, thymus, placenta, and lung (Day JR et al. 1994). Taking into account the organ size involved, liver and small intestine appear to be important sites of PLTP expression (Day JR et al. 1994; Jiang XC et al. 2012). It was also shown that PLTP is highly expressed in macrophages and in atherosclerotic lesions suggesting a potential role for this enzyme in lipid-loaded macrophages (Desrumaux CM et al. 2003; O'Brien KD et al. 2003; Laffitte BA et al. 2003; Vikstedt R et al. 2007). PLTP produced by macrophages may contribute to the optimal function of the ABCA1-mediated cholesterol efflux from macrophages to HDL (Oram JF et al. 2003; Lee-Rueckert M et al. 2006). PLTP is a direct target gene of liver X receptors (LXRα (NR1H3) and LXRβ (NR1H2)) which form functional heterodimers with the retinoid X receptor (RXR) (Laffitte BA et al. 2003; Mak PA et al. 2002; Cao G et al. 2002). NR1H2 &amp; NR1H3 act as cellular sensors of sterol levels and are transcriptionally activated by oxidized forms of cholesterol, oxysterols (Janowski BA et al. 1996). LXR agonists induced the expression of PLTP in various tissues of mice treated with synthetic LXR agonists, T0901317 or GW3965, in a coordinate manner with known LXR target genes (Cao G et al. 2002; Laffitte BA et al. 2003). PLTP expression was also highly induced by LXR (NR1H2 and NR1H3) and retinoid X receptor (RXR) agonists in murine peritoneal and human THP-1 macrophages (Mak PA et al. 2002; Laffitte BA et al. 2003). Regulation of PLTP by NR1H2 or NR1H3 ligands was abolished in animals or cells lacking both NR1H3 (LXRα) and NR1H2 (LXRβ) (Laffitte BA et al. 2003). Further, administration of the synthetic NR1H2, NR1H3 ligand T0901317 to mice elevated HDL cholesterol and phospholipid and generated enlarged HDL particles that were enriched in cholesterol, ApoAI, ApoE, and phospholipid (Cao G et al. 2002). This occured alongside with the increased plasma PLTP activity and liver PLTP mRNA levels (Cao G et al. 2002). Similar findings were reported for the regulation of PLTP levels in vivo by another synthetic NR1H2, NR1H3 ligand GW3965 (Laffitte BA et al. 2003). These data suggest that NR1H2, NR1H3 and their ligands may modulate plasma lipoprotein metabolism through control of PLTP activity (Laffitte BA et al. 2003; Mak PA et al. 2002; Cao G et al. 2002).&lt;p&gt;The gene expression of PLTP can be also regulated by other members of the nuclear receptor family of transcription factors: farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor α (PRARα ) (Laffitte BA et al. 2003; Mak PA et al. 2002; Tu AY &amp; Albers JJ 2001).</Comment> <BiopaxRef>c65</BiopaxRef> <BiopaxRef>b4c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1586.0" Y="994.0" /> <Point X="2077.0" Y="996.0" /> <Anchor Position="0.0" Shape="None" GraphId="c6fc4" /> <Anchor Position="0.99" Shape="None" GraphId="c17fe" /> <Anchor Position="0.5" Shape="None" GraphId="b634c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624365" /> </Interaction> <Interaction GraphId="ff0f7"> <Comment Source="Reactome">The ATP-binding cassette sub-family A member 1 (ABCA1) mRNA is translated to yield ABCA1 protein.&lt;p&gt;Synthetic agonists of liver X-receptors (LXRα, NR1H3 and LXRβ, NR1H2) or cholesterol-loading signiï¬�cantly induced the expression of ABCA1 protein in mouse RAW 264.7 and human THP-1 macrophage cell lines (Beyea MM et al. 2007; Ku CS et al. 2012). Similar regulation of ABCA1 protein expression by NR1H2, 3 agonists was observed in human peripheral blood-derived monocytes (Mauerer R et al. 2009). Treatment of THP-1 macrophages with endogenous (25-hydroxycholesterol) or synthetic (T0901317) ligands of NR1H2,3 stimulated both transcriptional and posttranscriptional pathways to enhance ABCA1 expression (Ignatova ID et al. 2013). Further, partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the NR1H2,3 agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux in THP-1 cells (Beyea MM et al. 2007). NR1H3 and NR1H2-induced expression of ABCA1 is thought to promote cellular cholesterol transfer to lipid-poor apolipoproteins such as ApoA1 and ApoE in the formation of nascent HDL particles (Ignatova ID et al. 2013; Vedhachalam C et al. 2007). Loss of ABCA1 in humans results in Tangier disease, a condition in which patients have extremely low levels of circulating HDL, massive accumulation of cholesterol in macrophages, and an increased risk for developing atherosclerosis (Rust S et al. 1999).&lt;p&gt;MicroRNAs miR-26 and miR-33 negatively regulate the translation of ABCA1 mRNA and thus repress the NR1H2, NR1H3-dependent cholesterol efflux from macrophages (Sun D et al. 2012; Rayner KJ et al. 2010). 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</bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="dcb"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18782758</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Direct interaction of nuclear liver X receptor-beta with ABCA1 modulates cholesterol efflux.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hozoji M, Munehira Y, Ikeda Y, Makishima M, Matsuo M, Kioka N, Ueda K.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f39"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">26984517</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Shimada A, Kimura H, Oida K, Kanehara H, Bando Y, Sakamoto S, Wakasugi T, Saga T, Ito Y, Kamiyama K, Mikami D, Iwano M, Hirano T, Yoshida H.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="bca"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8402897</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="a42"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">23519696</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">de Aguiar Vallim TQ, Tarling EJ, Kim T, Civelek M, Baldán Á, Esau C, Edwards PA.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="fad"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17684114</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Herzog B, Hallberg M, Seth A, Woods A, White R, Parker MG.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="fab"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11790787</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="a35"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11149950</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="d78"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17186944</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Beyea MM, Heslop CL, Sawyez CG, Edwards JY, Markle JG, Hegele RA, Huff MW.</bp:AUTHORS> </bp:PublicationXref> <bp:openControlledVocabulary xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#"> <bp:TERM xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">lipid signaling pathway</bp:TERM> <bp:ID xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PW:0000959</bp:ID> <bp:Ontology xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pathway Ontology</bp:Ontology> </bp:openControlledVocabulary> </Biopax> </Pathway>

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