Transcriptional regulation of white adipocyte differentiation (Homo sapiens)

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4, 9, 10, 12, 14...13, 20, 386, 15, 21, 318, 402416, 36, 39162, 7, 161616, 302, 16, 22, 30, 373424161, 3, 27, 3524241624nucleoplasmcytosollipid particleLPL geneMED11 FABP4 MED14 MED22 TGFB1NCOR2 PLIN1 geneMED20 RXRA CCNC SMARCD3 MED1 NCOA3CHD9 TBL1X SLC2A4 MED19 TBL1XR1 RXRA LPLNCOA1 CEBPANCOA1NCOA2KLF5GLUT4 tetramerMED4 NF-kB complexNCOA3 MED13 CREBBPRXRACEBPB GeneRGZ RXRA PPARG NCOA1 MED23 CCNC 9S-HODE CREBBP NCOA2 MED7 AA PPARG:RXRA:Corepressor ComplexCREBBP CDK19 EP300 9S-HODE MED18 MED27 MED25 MED6 HDAC3 MED29 ADIPOQMED31 13(S')-HODE EGR2CCND3HELZ2Palm CDK8 MED21 MED18 NCOR1 NCOA6 MED12 MED13 MED19 HDAC3MED12 MED16 CEBPD geneMED14 MED11 PPARGC1A PPARG MED1 RXRA Actos MED27 PPARA MED26 PPARG:RXRAHeterodimerKLF5 geneANGPTL geneMED9 PPARGMED15 TNF(77-233)MED13L LINA PLIN1EP300MED25 PPARGC1AFABP4ALA MED8 EBF1RELA CEBPA geneMED21 MED17 EPA EBF1 geneADIPOQ geneMED15 FABP4 geneNFKB1(1-433) CD36 geneCEBPDTGS1 MED7 MED24 MED9 ANGPTL4MED31 LEPMED30 MED24 HELZ2 MED16 PCK1CDK19 NR2F2FABP4PPARG MED22 MED20 CDK8 MED29 CARM1 13(S')-HODE PPARA:RXRACoactivator complexPPARG:FattyAcid:RXRA:Mediator:Coactivator ComplexMED13L CEBPBActos RGZ MED4 Mediator Complex(consensus)MED10 KLF4SREBF1A,2MED26 CDK4NCOR1PPARG geneMED23 MED8 MED10 LEP gene4xPalmC-CD36HELZ2 MED6 PCK1 geneMED1 SLC2A4 gene (GLUT4gene)NCOA2 MED17 NCOR2WNT1,WNT10BFABP4:Ligands ofPPARGMED30 5, 111833285, 11


Description

Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011).
Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes.
Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known.
CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research.
During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA.
PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994).
The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008).
Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes.
Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4 (SLC2A4)), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006).
Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG. Source:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
116666view12:48, 9 May 2021EweitzOntology Term : 'white fat cell' added !
114880view16:39, 25 January 2021ReactomeTeamReactome version 75
113326view11:39, 2 November 2020ReactomeTeamReactome version 74
112537view15:50, 9 October 2020ReactomeTeamReactome version 73
101450view11:32, 1 November 2018ReactomeTeamreactome version 66
100988view21:10, 31 October 2018ReactomeTeamreactome version 65
100524view19:44, 31 October 2018ReactomeTeamreactome version 64
100071view16:28, 31 October 2018ReactomeTeamreactome version 63
99622view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99229view12:44, 31 October 2018ReactomeTeamreactome version 62
93818view13:38, 16 August 2017ReactomeTeamreactome version 61
93364view11:21, 9 August 2017ReactomeTeamreactome version 61
88360view16:39, 1 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86448view09:18, 11 July 2016ReactomeTeamreactome version 56
83095view09:58, 18 November 2015ReactomeTeamVersion54
81767view10:12, 26 August 2015ReactomeTeamVersion53
76992view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76697view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76023view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75732view11:20, 10 June 2014ReactomeTeamReactome 48 Update
75082view14:03, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74729view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
13(S')-HODE MetaboliteCHEBI:34154 (ChEBI)
4xPalmC-CD36ProteinP16671 (Uniprot-TrEMBL)
9S-HODE MetaboliteCHEBI:34496 (ChEBI)
AA MetaboliteCHEBI:15843 (ChEBI)
ADIPOQ geneENSG00000181092 (ENSEMBL)
ADIPOQProteinQ15848 (Uniprot-TrEMBL)
ALA MetaboliteCHEBI:27432 (ChEBI)
ANGPTL geneENSG00000167772 (ENSEMBL)
ANGPTL4ProteinQ9BY76 (Uniprot-TrEMBL)
Actos MetaboliteCHEBI:8228 (ChEBI)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CCNC ProteinP24863 (Uniprot-TrEMBL)
CCND3ProteinP30281 (Uniprot-TrEMBL)
CD36 geneENSG00000135218 (ENSEMBL)
CDK19 ProteinQ9BWU1 (Uniprot-TrEMBL)
CDK4ProteinP11802 (Uniprot-TrEMBL)
CDK8 ProteinP49336 (Uniprot-TrEMBL)
CEBPA geneENSG00000245848 (ENSEMBL)
CEBPAProteinP49715 (Uniprot-TrEMBL)
CEBPB GeneENSG00000172216 (ENSEMBL)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CEBPD geneENSG00000221869 (ENSEMBL)
CEBPDProteinP49716 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
EBF1 geneENSG00000164330 (ENSEMBL)
EBF1ProteinQ9UH73 (Uniprot-TrEMBL)
EGR2ProteinP11161 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
FABP4 ProteinP15090 (Uniprot-TrEMBL)
FABP4 geneENSG00000170323 (ENSEMBL)
FABP4:Ligands of PPARGComplexR-HSA-2026090 (Reactome)
FABP4ProteinP15090 (Uniprot-TrEMBL)
GLUT4 tetramerComplexR-HSA-70384 (Reactome)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
HELZ2ProteinQ9BYK8 (Uniprot-TrEMBL)
KLF4ProteinO43474 (Uniprot-TrEMBL)
KLF5 geneENSG00000102554 (ENSEMBL)
KLF5ProteinQ13887 (Uniprot-TrEMBL)
LEP geneENSG00000174697 (ENSEMBL)
LEPProteinP41159 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
LPL geneENSG00000175445 (ENSEMBL)
LPLProteinP06858 (Uniprot-TrEMBL)
MED1 ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MED10 ProteinQ9BTT4 (Uniprot-TrEMBL)
MED11 ProteinQ9P086 (Uniprot-TrEMBL)
MED12 ProteinQ93074 (Uniprot-TrEMBL)
MED13 ProteinQ9UHV7 (Uniprot-TrEMBL)
MED13L ProteinQ71F56 (Uniprot-TrEMBL)
MED14 ProteinO60244 (Uniprot-TrEMBL)
MED15 ProteinQ96RN5 (Uniprot-TrEMBL)
MED16 ProteinQ9Y2X0 (Uniprot-TrEMBL)
MED17 ProteinQ9NVC6 (Uniprot-TrEMBL)
MED18 ProteinQ9BUE0 (Uniprot-TrEMBL)
MED19 ProteinA0JLT2 (Uniprot-TrEMBL)
MED20 ProteinQ9H944 (Uniprot-TrEMBL)
MED21 ProteinQ13503 (Uniprot-TrEMBL)
MED22 ProteinQ15528 (Uniprot-TrEMBL)
MED23 ProteinQ9ULK4 (Uniprot-TrEMBL)
MED24 ProteinO75448 (Uniprot-TrEMBL)
MED25 ProteinQ71SY5 (Uniprot-TrEMBL)
MED26 ProteinO95402 (Uniprot-TrEMBL)
MED27 ProteinQ6P2C8 (Uniprot-TrEMBL)
MED29 ProteinQ9NX70 (Uniprot-TrEMBL)
MED30 ProteinQ96HR3 (Uniprot-TrEMBL)
MED31 ProteinQ9Y3C7 (Uniprot-TrEMBL)
MED4 ProteinQ9NPJ6 (Uniprot-TrEMBL)
MED6 ProteinO75586 (Uniprot-TrEMBL)
MED7 ProteinO43513 (Uniprot-TrEMBL)
MED8 ProteinQ96G25 (Uniprot-TrEMBL)
MED9 ProteinQ9NWA0 (Uniprot-TrEMBL)
Mediator Complex (consensus)ComplexR-HSA-556786 (Reactome) The Mediator Complex bridges transcription factors and the basal RNA polymerase II complex. Multiple analyses of immunoprecipitated complexes from human cells (HeLa cells) detects 31 subunits. Other complexes with fewer subunits may also exist.
NCOA1 ProteinQ15788 (Uniprot-TrEMBL)
NCOA1ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 ProteinQ15596 (Uniprot-TrEMBL)
NCOA2ProteinQ15596 (Uniprot-TrEMBL)
NCOA3 ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA3ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR1ProteinO75376 (Uniprot-TrEMBL)
NCOR2 ProteinQ9Y618 (Uniprot-TrEMBL)
NCOR2ProteinQ9Y618 (Uniprot-TrEMBL)
NF-kB complexComplexR-HSA-194047 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NR2F2ProteinP24468 (Uniprot-TrEMBL)
PCK1 geneENSG00000124253 (ENSEMBL)
PCK1ProteinP35558 (Uniprot-TrEMBL)
PLIN1 geneENSG00000166819 (ENSEMBL)
PLIN1ProteinO60240 (Uniprot-TrEMBL)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
PPARG ProteinP37231 (Uniprot-TrEMBL)
PPARG geneENSG00000132170 (ENSEMBL)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexComplexR-HSA-381367 (Reactome)
PPARG:RXRA HeterodimerComplexR-HSA-381281 (Reactome)
PPARG:RXRA:Corepressor ComplexComplexR-HSA-381226 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGProteinP37231 (Uniprot-TrEMBL)
Palm MetaboliteCHEBI:15756 (ChEBI)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RGZ MetaboliteCHEBI:50122 (ChEBI)
RXRA ProteinP19793 (Uniprot-TrEMBL)
RXRAProteinP19793 (Uniprot-TrEMBL)
SLC2A4 ProteinP14672 (Uniprot-TrEMBL)
SLC2A4 gene (GLUT4 gene)ENSG00000181856 (ENSEMBL)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
SREBF1A,2R-HSA-1655734 (Reactome)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TGFB1ProteinP01137 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
TNF(77-233)ProteinP01375 (Uniprot-TrEMBL)
WNT1,WNT10BR-HSA-976184 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xPalmC-CD36ArrowR-HSA-560517 (Reactome)
ADIPOQ geneR-HSA-1183058 (Reactome)
ADIPOQArrowR-HSA-1183058 (Reactome)
ANGPTL geneR-HSA-560473 (Reactome)
ANGPTL4ArrowR-HSA-560473 (Reactome)
ArrowR-HSA-1183058 (Reactome)
ArrowR-HSA-560491 (Reactome)
CCND3ArrowR-HSA-560510 (Reactome)
CD36 geneR-HSA-560517 (Reactome)
CDK4ArrowR-HSA-560510 (Reactome)
CEBPA geneR-HSA-560491 (Reactome)
CEBPAArrowR-HSA-1183003 (Reactome)
CEBPAArrowR-HSA-1183032 (Reactome)
CEBPAArrowR-HSA-1183058 (Reactome)
CEBPAArrowR-HSA-381268 (Reactome)
CEBPAArrowR-HSA-560491 (Reactome)
CEBPB GeneR-HSA-381337 (Reactome)
CEBPBArrowR-HSA-1183058 (Reactome)
CEBPBArrowR-HSA-381283 (Reactome)
CEBPBArrowR-HSA-381337 (Reactome)
CEBPBArrowR-HSA-381377 (Reactome)
CEBPBArrowR-HSA-977271 (Reactome)
CEBPD geneR-HSA-977392 (Reactome)
CEBPDArrowR-HSA-381283 (Reactome)
CEBPDArrowR-HSA-381377 (Reactome)
CEBPDArrowR-HSA-977271 (Reactome)
CEBPDArrowR-HSA-977392 (Reactome)
CREBBPR-HSA-381309 (Reactome)
EBF1 geneR-HSA-977271 (Reactome)
EBF1ArrowR-HSA-381283 (Reactome)
EBF1ArrowR-HSA-977271 (Reactome)
EGR2ArrowR-HSA-381337 (Reactome)
EP300R-HSA-381309 (Reactome)
FABP4 geneR-HSA-560510 (Reactome)
FABP4:Ligands of PPARGR-HSA-381309 (Reactome)
FABP4ArrowR-HSA-381309 (Reactome)
FABP4ArrowR-HSA-560510 (Reactome)
GLUT4 tetramerArrowR-HSA-1183032 (Reactome)
HDAC3ArrowR-HSA-381309 (Reactome)
HDAC3R-HSA-381290 (Reactome)
HELZ2R-HSA-381309 (Reactome)
KLF4ArrowR-HSA-381337 (Reactome)
KLF5 geneR-HSA-381377 (Reactome)
KLF5ArrowR-HSA-381283 (Reactome)
KLF5ArrowR-HSA-381377 (Reactome)
LEP geneR-HSA-1183003 (Reactome)
LEPArrowR-HSA-1183003 (Reactome)
LPL geneR-HSA-560498 (Reactome)
LPLArrowR-HSA-560498 (Reactome)
Mediator Complex (consensus)R-HSA-381309 (Reactome)
NCOA1R-HSA-381309 (Reactome)
NCOA2R-HSA-381309 (Reactome)
NCOA3R-HSA-381309 (Reactome)
NCOR1ArrowR-HSA-381309 (Reactome)
NCOR1R-HSA-381290 (Reactome)
NCOR2ArrowR-HSA-381309 (Reactome)
NCOR2R-HSA-381290 (Reactome)
PCK1 geneR-HSA-560472 (Reactome)
PCK1ArrowR-HSA-560472 (Reactome)
PLIN1 geneR-HSA-560493 (Reactome)
PLIN1ArrowR-HSA-560493 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-560473 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-560517 (Reactome)
PPARG geneR-HSA-381268 (Reactome)
PPARG geneR-HSA-381283 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-381309 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560472 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560473 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560491 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560493 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560498 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560510 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560517 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexTBarR-HSA-1183003 (Reactome)
PPARG:RXRA HeterodimerArrowR-HSA-381262 (Reactome)
PPARG:RXRA HeterodimerR-HSA-381290 (Reactome)
PPARG:RXRA:Corepressor ComplexArrowR-HSA-381290 (Reactome)
PPARG:RXRA:Corepressor ComplexR-HSA-381309 (Reactome)
PPARG:RXRA:Corepressor ComplexTBarR-HSA-1183032 (Reactome)
PPARGArrowR-HSA-381268 (Reactome)
PPARGArrowR-HSA-381283 (Reactome)
PPARGC1AR-HSA-381309 (Reactome)
PPARGR-HSA-381262 (Reactome)
R-HSA-1183003 (Reactome) The Ob gene encoding leptin is transcribed to yield mRNA and translated to yield protein. Expression of leptin is positively regulated by C/EBPalpha (CEBPA, Miller et al. 1996, Melzner et al. 2002) and negatively regulated by PPARG in adipocytes (De Vos et al. 1996).
R-HSA-1183032 (Reactome) The GLUT4 (SLC2A4) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1183058 (Reactome) The Adiponectin gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Adiponectin is upregulated during adipogenesis by C/EBPalpha (CEBPA), PPARG, and CEBPB (Segawa et al. 2009, Qiao et al. 2005, Iwaki et al. 2003, Kita et al. 2005).
R-HSA-381262 (Reactome) PPARG binds the Retinoic acid X Receptor RXRA to form a heterodimer that has transcriptional acivation activity. The complex was initially called ARF6 when discovered. PPARG binds RXRA via the C-terminus and AF-2 regions of PPARG.
R-HSA-381268 (Reactome) In mouse, by 10 days after induction of adipocyte differentiation Cebpa, but neither Cebpb nor Cebpd, is detectable at the Pparg promoter. While adipocyte differentiation can proceed without Cebpa, adipocytes differentiated from Cebpa-knockout cells are insulin insensitive due to a defect in Glut4 (Slc2a4) vesicle trafficking.
R-HSA-381283 (Reactome) The transcription factors CEBPB, CEBPD, and KLF5 simultaneously bind the PPARG promoter and synergistically activate transcription of the PPARG gene. These three factors activate transcription after initial stimulation of adipocyte differentiation but then are replaced by CEBPA within 10 days. CEBPA and other factors may be responsible for long term maintenance of PPARG expression and the differentiated state.
Pre-adipose tissue contains both the widely expressed PPARG isoform 1 mRNA and the more tissue-specific PPARG isoform 2. The PPARG isoform 2 mRNA is translated to yield PPARG isoform 2 protein, which has 505 amino acid residues (57 KDa) and is the longest of the 4 observed variants. Isoform 2 is specific to preadipose and adipose tissue (Mukherjee et al. 1997). Confusingly, the longest variant is called isoform 1 in some publications.
R-HSA-381290 (Reactome) The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state.
R-HSA-381309 (Reactome) PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996).
FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010).
Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010).
The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL).
R-HSA-381337 (Reactome) Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:
1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.
2) Glucocorticoids activate expression of CEBPD.
3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.
The detailed mechanisms of activation are not yet known.
R-HSA-381377 (Reactome) Increased expression of KLF5 occurs after activation of the transcription factors CEBPB and CEBPD during differentiation and activation of KLF5 depends on CEBPB and CEBPD. Both CEBPB and CEBPD bind the promoter of the KLF5 gene upstream of the site of transcription initiation and activate transcription of KLF5.
R-HSA-560472 (Reactome) The PEPCK-C gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560473 (Reactome) The ANGPTL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560491 (Reactome) The CEBPA gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560493 (Reactome) The Perilipin (PLIN) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Perilipin is upregulated during adipogenesis.
R-HSA-560498 (Reactome) The LPL gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560510 (Reactome) The FABP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of FABP4 is activated during adipogenesis.
R-HSA-560517 (Reactome) The Platelet glycoprotein IV gene (CD36, PAS IV, GPIV) is transcribed to yield mRNA and the mRNA is translated to yield proteind.
R-HSA-977271 (Reactome) The gene encoding transcription factor EBF1 is transcribed to yield mRNA and the mRNA is translated to yield protein in pre-adipocytes and adipocytes. Transcription of EBF1 is enhanced by CEBPB and CEBPD, which bind the EBF1 promoter.
R-HSA-977392 (Reactome) Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:
1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.
2) Glucocorticoids activate expression of CEBPD.
3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.
The detailed mechanisms of activation are not yet known.
RXRAR-HSA-381262 (Reactome)
SLC2A4 gene (GLUT4 gene)R-HSA-1183032 (Reactome)
SREBF1A,2ArrowR-HSA-381283 (Reactome)
TBarR-HSA-381283 (Reactome)
TGFB1TBarR-HSA-381283 (Reactome)
TGFB1TBarR-HSA-560491 (Reactome)
TNF(77-233)TBarR-HSA-560491 (Reactome)
WNT1,WNT10BTBarR-HSA-560491 (Reactome)
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