Plasma lipoprotein assembly, remodeling, and clearance (Homo sapiens)

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endocytic vesicle membranecytosoltransport vesicle membraneAPOA2(24-100) APOA1(25-266) NPC1Clathrin:AP-2complexApoB-48:TG:PLcomplexAP2B1 LDLR TAGs CHEST LSR APOA1(25-266) CHEST pre-beta HDLCHEST LIPG TAGs VLDL (-APOC1,C4)LDLR 4xPALM-C-p-2S-ABCA1tetramer:APOA1CHOLLCFA(-)TAGs LSR trimer:LDLAPOA1(25-266) APOC2 gene PLAPOE APOB(28-4563) TAGsPL PCSK9:LDLRAPOB(28-2179) PCSK5TAGs PL CLTA CHOL TAGs TAGs CHOL CLTC APOB(28-4563) A2M APOC2 cholesterol LDLRAP1NR1H3 AMN APOB(28-4563) APOA4 CHOL LDL:cholesterolester complexLDLRHSPGLIPC dimerAPOA2(24-100) LDL:LDLR complexCHEST TAGs cholesterol esters A2M tetramerTAGs APOB(28-4563) SOAT2 MYLIP dimerAPOA1(19-266)APOB(28-4563) PL CHOL PALM-CoAAPOA1(25-266) CHOL APOB(28-4563) ANGPTL3 APOB(28-2179) APOA1(25-266) SAR1BVLDL:PCSK9:Clathrin:AP2PL CHOL PL APOC4CHOL APOBR dimerCHOLAPOA1(25-266) LCATH2OH2OAP2S1 APOA5PCSK9 APOC2 LPACHESTLDLR CHOL AP2A1 PL APOB(28-4563) AP2M1 AP2A1 AP2M1 PL NCEH1APOB(28-2179)TAGs CHEST PLAPOA4 gene PL PL NR1H2 APOB(28-4563) TAGs nascent chylomicronLMF1 PL CHEST HDLBP PCSK9:LDLR:Clathrin:AP2pre-VLDLPL P4HB PL MBTPS1,2VLDLR APOC3 PL TAGs AP2M1 LDLRLDLR APOB(28-4563) CHOL SCARB1-2LSR trimerCHOLANGPTL4PL CHOL APOC1 LSR LSR TAG CREB3L3(1-?)PCSK9 GPIHBP1 PL VLDL:PCSK9:Clathrin:AP2HDLBP:HDLchylomicronremnant:apoE:LDLRcomplex4xPALM-C-ABCA1 PL LDLR 4xPALM-C-ABCA1 FURIN,PCSK6LDLRAP1TAGsAPOB(28-4563)1-acyl LPCPL CHEST SOAT1 CHEST APOC1SCARB1-2 APOC3sphericalHDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-IIITAGs CLTC PL PRKACA TAGs PRKACG APOB(28-2179) VLDLR CHOLAP2A2(1-939) 4xPALM-C-ABCA1tetramerFAsPLVLDLRLDLR LPL dimerLIPC dimerAPOC1 CHEST PL TAGs CHEST pre-VLDLCETP AP2A2(1-939) spherical HDLPLTP-2 LCAT:spherical HDLcomplexCHOLCHOL APOE LCFAsCoA-SHPCSK6 TAGs PL PL TAGs APOB(28-2179) TAGs PCSK9APOA1(25-266) FGF21 cholesterol esters PL LDLR CUBN CLTA TAGs MYLIP CHOL AP2A2(1-939) ANGPTL8 sphericalHDL:triacylglycerolcomplexTAGs PL PL APOA5 gene spherical HDLPLCHOL MTP:PDI:lipidcomplexAPOE ANGPTL8GPIHBP1:HSPG:LPLdimerCHESTAPOA1(25-266) APOA5 DAGsNPC2 APOA1(25-267)TAGs TAGs APOA1(25-267) APOC3 LDLR AP2S1 ANGPTL3:ANGPTL8VLDLCHOL APOA1(25-266) CLTC PCSK9 Clathrin:AP-2complexAPOA1(25-266) APOA4 AP2A1 CoA-SHClathrin:AP2 complexAP2S1 CHOLCLTC CHEST MBTPS2 AMN LSR trimer:VLDLAPOA1(25-266) FURIN VLDL:PCSK9APOA4 spherical HDL4xPALM-C-ABCA1tetramerPCSK9LSR CHEST VLDLR AP2A1 TAGs APOA1(25-266) LDLcholesterol torcetrapib AP2M1 discoidal HDLLCAT:discoidal HDLcomplexCETP APOC2 APOA1(25-266)APOA1(25-266) APOA4chylomicronremnant:apoE:LDLRcomplexTAGs AP2B1 CHOL CLTC APOB(28-4563) APOA1(25-266) TAGs APOA4 AP2M1 APOA4 H2OCIDEC gene CHEST AP2B1 H2OCHESTCREB3L3(1-?)PLTPcholesterol esters CHEST LIPCCHOL PL CHOLCHEST LDLR CHOL CHEST LPL CIDEC APOFALB APOBR ATPAPOC2SOAT1,2TAGs TAG TAGs CHEST TAGs PL PL APOC3 Lp(a)PCSK9:LDLR:Clathrin:AP2CETP:cholesterolester complexCHOL TAGs APOC4 GPIHBP1CETP CHOL PLTP-1 CHEST phosphatidylcholinesTAGs APOC2 spherical HDL:SR-BIcomplexAPOB(28-2179) APOBR dimer:VLDLAPOB(28-4563) APOB(28-4563) TAGs chylomicronremnant:apoE:LDLRcomplexMBTPS1 PL AP2S1 APOEABCG1 LCATCHEST TAGsCHOL VLDLTAGs CHEST APOE CHEST CHEST APOA1(25-266)APOA1(25-266)BMP1-3 ANGPTL3AP2M1 CHOL CHEST PRKACB PL CHOL TAGsLDLRLCAT CLTA LIPC dimer:heparinPL APOB(28-4563) CETP:sphericalHDL:torcetrapibcomplexAP2S1 PL HDLBPPL CHEST PL cholesterol esters CHOL APOA1(25-266) HSPG APOC3 CHOL LMF1 LMF1,2enlarged sphericalHDLZDHHC8cholesterol cholesterol APOETAGs CHOL LIPC APOC2TAG PCSK9 1-acyl LPC LSR trimerPL APOC2 MTP:PDI:lipidcomplexAP2S1 TAGP4HB PL NPC2CHEST AP2B1 APOB(28-4563) PL LDLAPOC4 ABCA1 cholesterol esters chylomicron remnantBMP1-3:Zn2+APOA2(24-100) PKA catalyticsubunitCHOLTAGsTAGs PL VLDLR TG-depletedchylomicronLIPC MTTP chylomicronAPOC1 AP2B1 PLAP2A2(1-939) APOB(28-2179) APOB(28-2179) APOB(28-2179) pre-beta HDLCLTA LMF2 AP2A2(1-939) TAGs Heparins ADPPL APOC1 cholesterol estersAPOA1(25-266) NR1H2,NR1H3CLTC ABCA1 tetramerHSPG CLTC CHOL ALBDAGstorcetrapibCHESTUb-K839-VLDLRAPOB(28-2179) PL APOC3 LDLRCHOL LIPC PL AP2A1 4xPALM-C-p-2S-ABCA1 APOB(28-2179) LCFAsPL APOA1(25-266) PL APOA2(24-100)TAGs TAGs sphericalHDL:apoC-II:apoC-III:apoELPL APOB(28-4563) VLDL:VLDLRCHOL TAGs 4xPALM-C-p-2S-ABCA1tetramerVLDLRCHOL ABCG1 dimerPLTAGs nascent chylomicronAPOB(28-4563) MTTP LDL:LDLR complexATPCREB3L3cholesterol esters NPC2:CHOLAPOB(28-2179) Zn2+ CLTA CREB3L3(?-461)LMF2 APOE LIPC AP2S1 CHOLCUBN:AMNPL cholesterol PL APOA1(25-266) LIPAAP2A1 AP2A2(1-939) ADPAP2M1 cholesterol esters DAGsLPA LIPC dimer:LMF1,2PLCES3CHEST PCSK9 PL TAGs CHOL apoA-I:CUBN:AMNcomplexPL CHEST APOB(28-4563) CHOLPL AP2A2(1-939) HeparinsAP2B1 APOA1(25-266) cholesterol esters CHOL ADPAPOA1(25-266) cholesterol H2OApoB-48:TG:PLcomplexCHOL PL CLTA PCSK9 CHOL APOA1(25-266) CHOL LIPG dimerAPOC4 discoidalHDL:cholesterolLDL:LDLR complexCHESTAPOC4 PL FAHSPG:LPL dimerAPOC2 ATPAPOE LPLAP2A1 4xPALM-C-p-2S-ABCA1 TAGs LCAT CHEST CHOL LPL acyl-CoATAGsAPOA1(25-266) APOE albumin:2-lysophosphatidylcholine complexCHOL LDLAPOE cholesterol esters APOA2(24-100) PiCHOL CHOL sphericalHDL:apoC-II:apoC-III:apoEFGF21 gene APOB(28-2179) chylomicronremnant:apoEcomplexchylomicronremnant:apoEcomplexPiH2OCHEST TAGs APOA4,APOA5,APOC2,CIDEC,FGF21APOC3APOE spherical HDLAPOB(28-2179)LIPA-degraded LDLPL CHEST PL APOA2(24-100) CETP:triacylglycerolcomplexCHOL PL APOA4,APOA5,APOC2,CIDEC,FGF21 genesCHOL TAGs CHEST APOB(28-4563) CLTA TAGs AP2B1 CUBN NPC1 NPC1:CHOLAPOE APOBR APOA4 CHOLAPOA1(25-266) CHEST 134911341341341341341341345713411757134134134


Description

Because of their hydrophobicity, lipids are found in the extracellular spaces of the human body primarily in the form of lipoprotein complexes. Chylomicrons form in the small intestine and transport dietary lipids to other tissues in the body. Very low density lipoproteins (VLDL) form in the liver and transport triacylglycerol synthesized there to other tissues of the body. As they circulate, VLDL are acted on by lipoprotein lipases on the endothelial surfaces of blood vessels, liberating fatty acids and glycerol to be taken up by tissues and converting the VLDL first to intermediate density lipoproteins (IDL) and then to low density lipoproteins (LDL). IDL and LDL are cleared from the circulation via a specific cell surface receptor, found in the body primarily on the surfaces of liver cells. High density lipoprotein (HDL) particles, initially formed primarily by the liver, shuttle several kinds of lipids between tissues and other lipoproteins. Notably, they are responsible for the so-called reverse transport of cholesterol from peripheral tissues to LDL for return to the liver.

Three aspects of lipoprotein function are currently annotated in Reactome: chylomicron-mediated lipid transport, LDL endocytosis and degradation, and HDL-mediated lipid transport, each divided into assembly, remodeling, and clearance subpathways. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 174824
Reactome-version 
Reactome version: 63
Reactome Author 
Reactome Author: D'Eustachio, Peter

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  69. Peterson J, Fujimoto WY, Brunzell JD.; ''Human lipoprotein lipase: relationship of activity, heparin affinity, and conformation as studied with monoclonal antibodies.''; PubMed Europe PMC Scholia
  70. Zhao B, Bie J, Wang J, Marqueen SA, Ghosh S.; ''Identification of a novel intracellular cholesteryl ester hydrolase (carboxylesterase 3) in human macrophages: compensatory increase in its expression after carboxylesterase 1 silencing.''; PubMed Europe PMC Scholia
  71. Singaraja RR, Kang MH, Vaid K, Sanders SS, Vilas GL, Arstikaitis P, Coutinho J, Drisdel RC, El-Husseini Ael D, Green WN, Berthiaume L, Hayden MR.; ''Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function.''; PubMed Europe PMC Scholia
  72. Fielding CJ, Shore VG, Fielding PE.; ''A protein cofactor of lecithin:cholesterol acyltransferase.''; PubMed Europe PMC Scholia
  73. Bradley WA, Brown ML, Ramprasad MP, Li R, Song R, Gianturco SH.; ''Antipeptide antibodies reveal interrelationships of MBP 200 and MBP 235: unique apoB-specific receptors for triglyceride-rich lipoproteins on human monocyte-macrophages.''; PubMed Europe PMC Scholia
  74. Holmes RS, Cox LA, VandeBerg JL.; ''Mammalian carboxylesterase 3: comparative genomics and proteomics.''; PubMed Europe PMC Scholia
  75. Ren G, Kim JY, Smas CM.; ''Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism.''; PubMed Europe PMC Scholia
  76. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, Rudling M, Myrdal U, Annesi G, Naik S, Meadows N, Quattrone A, Islam SA, Naoumova RP, Angelin B, Infante R, Levy E, Roy CC, Freemont PS, Scott J, Shoulders CC.; ''Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.''; PubMed Europe PMC Scholia
  77. Michaely P, Li WP, Anderson RG, Cohen JC, Hobbs HH.; ''The modular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.''; PubMed Europe PMC Scholia
  78. Li Y, Teng C.; ''Angiopoietin-like proteins 3, 4 and 8: regulating lipid metabolism and providing new hope for metabolic syndrome.''; PubMed Europe PMC Scholia
  79. Wu X, Zhou M, Huang LS, Wetterau J, Ginsberg HN.; ''Demonstration of a physical interaction between microsomal triglyceride transfer protein and apolipoprotein B during the assembly of ApoB-containing lipoproteins.''; PubMed Europe PMC Scholia
  80. Chin KT, Zhou HJ, Wong CM, Lee JM, Chan CP, Qiang BQ, Yuan JG, Ng IO, Jin DY.; ''The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.''; PubMed Europe PMC Scholia
  81. Chang TY, Li BL, Chang CC, Urano Y.; ''Acyl-coenzyme A:cholesterol acyltransferases.''; PubMed Europe PMC Scholia
  82. Denis M, Haidar B, Marcil M, Bouvier M, Krimbou L, Genest J.; ''Characterization of oligomeric human ATP binding cassette transporter A1. Potential implications for determining the structure of nascent high density lipoprotein particles.''; PubMed Europe PMC Scholia
  83. Zhu M, Zhao X, Chen J, Xu J, Hu G, Guo D, Li Q, Zhang X, Chang CC, Song B, Xiong Y, Chang T, Li B.; ''ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-α-processing alteration.''; PubMed Europe PMC Scholia
  84. Marschner K, Kollmann K, Schweizer M, Braulke T, Pohl S.; ''A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism.''; PubMed Europe PMC Scholia
  85. Murao K, Terpstra V, Green SR, Kondratenko N, Steinberg D, Quehenberger O.; ''Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.''; PubMed Europe PMC Scholia
  86. Paule S, Aljofan M, Simon C, Rombauts LJ, Nie G.; ''Cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6.''; PubMed Europe PMC Scholia
  87. Yen FT, Roitel O, Bonnard L, Notet V, Pratte D, Stenger C, Magueur E, Bihain BE.; ''Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice.''; PubMed Europe PMC Scholia
  88. Péterfy M, Ben-Zeev O, Mao HZ, Weissglas-Volkov D, Aouizerat BE, Pullinger CR, Frost PH, Kane JP, Malloy MJ, Reue K, Pajukanta P, Doolittle MH.; ''Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia.''; PubMed Europe PMC Scholia
  89. Jackson RL, Tajima S, Yamamura T, Yokoyama S, Yamamoto A.; ''Comparison of apolipoprotein C-II-deficient triacylglycerol-rich lipoproteins and trioleoylglycerol/phosphatidylcholine-stabilized particles as substrates for lipoprotein lipase.''; PubMed Europe PMC Scholia
  90. Sakai K, Igarashi M, Yamamuro D, Ohshiro T, Nagashima S, Takahashi M, Enkhtuvshin B, Sekiya M, Okazaki H, Osuga J, Ishibashi S.; ''Critical role of neutral cholesteryl ester hydrolase 1 in cholesteryl ester hydrolysis in murine macrophages.''; PubMed Europe PMC Scholia
  91. Havel RJ, Kane JP, Kashyap ML.; ''Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man.''; PubMed Europe PMC Scholia
  92. See RH, Caday-Malcolm RA, Singaraja RR, Zhou S, Silverston A, Huber MT, Moran J, James ER, Janoo R, Savill JM, Rigot V, Zhang LH, Wang M, Chimini G, Wellington CL, Tafuri SR, Hayden MR.; ''Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux.''; PubMed Europe PMC Scholia
  93. Hill JS, Davis RC, Yang D, Schotz MC, Wong H.; ''Hepatic lipase: high-level expression and subunit structure determination.''; PubMed Europe PMC Scholia
  94. Beigneux AP, Fong LG, Bensadoun A, Davies BS, Oberer M, Gårdsvoll H, Ploug M, Young SG.; ''GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding.''; PubMed Europe PMC Scholia
  95. Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, Boyadjian R, Rodenburg KW, Foley E, Korhonen L, Lindholm D, Nimpf J, van Berkel TJ, Tontonoz P, Zelcer N.; ''The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.''; PubMed Europe PMC Scholia
  96. Sorrentino V, Zelcer N.; ''Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor.''; PubMed Europe PMC Scholia
  97. Switzer S, Eder HA.; ''Transport of lysolecithin by albumin in human and rat plasma.''; PubMed Europe PMC Scholia
  98. Fielding CJ, Shore VG, Fielding PE.; ''Lecithin: cholesterol acyltransferase: effects of substrate composition upon enzyme activity.''; PubMed Europe PMC Scholia
  99. Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH.; ''Atypical angiopoietin-like protein that regulates ANGPTL3.''; PubMed Europe PMC Scholia
  100. Oeffner F, Fischer G, Happle R, König A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casaño A, Weirich C, Grzeschik KH.; ''IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.''; PubMed Europe PMC Scholia
  101. Dubland JA, Francis GA.; ''Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism.''; PubMed Europe PMC Scholia
  102. Vaughan AM, Oram JF.; ''ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins.''; PubMed Europe PMC Scholia
  103. Eden ER, Patel DD, Sun XM, Burden JJ, Themis M, Edwards M, Lee P, Neuwirth C, Naoumova RP, Soutar AK.; ''Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.''; PubMed Europe PMC Scholia
  104. Wang J, Hegele RA.; ''Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650).''; PubMed Europe PMC Scholia
  105. Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P, Reue K, Bensadoun A, Fong LG, Beigneux AP.; ''GPIHBP1, an endothelial cell transporter for lipoprotein lipase.''; PubMed Europe PMC Scholia
  106. Bocharov AV, Vishnyakova TG, Baranova IN, Patterson AP, Eggerman TL.; ''Characterization of a 95 kDa high affinity human high density lipoprotein-binding protein.''; PubMed Europe PMC Scholia
  107. Silver DL, Tall AR.; ''The cellular biology of scavenger receptor class B type I.''; PubMed Europe PMC Scholia
  108. Hegele RA, Tu L, Connelly PW.; ''Human hepatic lipase mutations and polymorphisms.''; PubMed Europe PMC Scholia
  109. Takahashi K, Takeya M, Sakashita N.; ''Multifunctional roles of macrophages in the development and progression of atherosclerosis in humans and experimental animals.''; PubMed Europe PMC Scholia
  110. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG.; ''The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.''; PubMed Europe PMC Scholia
  111. Yen FT, Masson M, Clossais-Besnard N, André P, Grosset JM, Bougueleret L, Dumas JB, Guerassimenko O, Bihain BE.; ''Molecular cloning of a lipolysis-stimulated remnant receptor expressed in the liver.''; PubMed Europe PMC Scholia
  112. Gianturco SH, Ramprasad MP, Song R, Li R, Brown ML, Bradley WA.; ''Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor.''; PubMed Europe PMC Scholia
  113. Lee AH.; ''The role of CREB-H transcription factor in triglyceride metabolism.''; PubMed Europe PMC Scholia
  114. Fernández-Borja M, Bellido D, Vilella E, Olivecrona G, Vilaró S.; ''Lipoprotein lipase-mediated uptake of lipoprotein in human fibroblasts: evidence for an LDL receptor-independent internalization pathway.''; PubMed Europe PMC Scholia
  115. Sakai J, Hoshino A, Takahashi S, Miura Y, Ishii H, Suzuki H, Kawarabayasi Y, Yamamoto T.; ''Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.''; PubMed Europe PMC Scholia
  116. Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP.; ''Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.''; PubMed Europe PMC Scholia
  117. Igarashi M, Osuga J, Uozaki H, Sekiya M, Nagashima S, Takahashi M, Takase S, Takanashi M, Li Y, Ohta K, Kumagai M, Nishi M, Hosokawa M, Fledelius C, Jacobsen P, Yagyu H, Fukayama M, Nagai R, Kadowaki T, Ohashi K, Ishibashi S.; ''The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages.''; PubMed Europe PMC Scholia
  118. Oram JF, Wolfbauer G, Vaughan AM, Tang C, Albers JJ.; ''Phospholipid transfer protein interacts with and stabilizes ATP-binding cassette transporter A1 and enhances cholesterol efflux from cells.''; PubMed Europe PMC Scholia
  119. Hegele RA, Little JA, Vezina C, Maguire GF, Tu L, Wolever TS, Jenkins DJ, Connelly PW.; ''Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics.''; PubMed Europe PMC Scholia
  120. Wang X, Driscoll DM, Morton RE.; ''Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F.''; PubMed Europe PMC Scholia
  121. Du H, Sheriff S, Bezerra J, Leonova T, Grabowski GA.; ''Molecular and enzymatic analyses of lysosomal acid lipase in cholesteryl ester storage disease.''; PubMed Europe PMC Scholia
  122. Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM.; ''Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide.''; PubMed Europe PMC Scholia
  123. Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC, Hobbs HH.; ''Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.''; PubMed Europe PMC Scholia
  124. Berryman DE, Bensadoun A.; ''Heparan sulfate proteoglycans are primarily responsible for the maintenance of enzyme activity, binding, and degradation of lipoprotein lipase in Chinese hamster ovary cells.''; PubMed Europe PMC Scholia
  125. Vedhachalam C, Duong PT, Nickel M, Nguyen D, Dhanasekaran P, Saito H, Rothblat GH, Lund-Katz S, Phillips MC.; ''Mechanism of ATP-binding cassette transporter A1-mediated cellular lipid efflux to apolipoprotein A-I and formation of high density lipoprotein particles.''; PubMed Europe PMC Scholia
  126. Kozyraki R, Fyfe J, Kristiansen M, Gerdes C, Jacobsen C, Cui S, Christensen EI, Aminoff M, de la Chapelle A, Krahe R, Verroust PJ, Moestrup SK.; ''The intrinsic factor-vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein.''; PubMed Europe PMC Scholia
  127. Nakagawa M, Nishida T.; ''Effect of lysolecithin and albumin on lecithin-cholesterol acyltransferase activity in human plasma.''; PubMed Europe PMC Scholia
  128. Tiwari S, Siddiqi SA.; ''Intracellular trafficking and secretion of VLDL.''; PubMed Europe PMC Scholia
  129. Lobentanz EM, Krasznai K, Gruber A, Brunner C, Müller HJ, Sattler J, Kraft HG, Utermann G, Dieplinger H.; ''Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.''; PubMed Europe PMC Scholia
  130. Becker A, Böttcher A, Lackner KJ, Fehringer P, Notka F, Aslanidis C, Schmitz G.; ''Purification, cloning, and expression of a human enzyme with acyl coenzyme A: cholesterol acyltransferase activity, which is identical to liver carboxylesterase.''; PubMed Europe PMC Scholia
  131. Chan CP, Mak TY, Chin KT, Ng IO, Jin DY.; ''N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H.''; PubMed Europe PMC Scholia
  132. Igarashi M, Osuga J, Isshiki M, Sekiya M, Okazaki H, Takase S, Takanashi M, Ohta K, Kumagai M, Nishi M, Fujita T, Nagai R, Kadowaki T, Ishibashi S.; ''Targeting of neutral cholesterol ester hydrolase to the endoplasmic reticulum via its N-terminal sequence.''; PubMed Europe PMC Scholia
  133. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino RB, Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M.; ''Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis.''; PubMed Europe PMC Scholia
  134. Chau P, Nakamura Y, Fielding CJ, Fielding PE.; ''Mechanism of prebeta-HDL formation and activation.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114663view16:13, 25 January 2021ReactomeTeamReactome version 75
113111view11:17, 2 November 2020ReactomeTeamReactome version 74
112345view15:27, 9 October 2020ReactomeTeamReactome version 73
101245view11:14, 1 November 2018ReactomeTeamreactome version 66
100784view20:41, 31 October 2018ReactomeTeamreactome version 65
100326view19:18, 31 October 2018ReactomeTeamreactome version 64
99871view16:01, 31 October 2018ReactomeTeamreactome version 63
99428view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93663view11:30, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
1-acyl LPC MetaboliteCHEBI:17504 (ChEBI)
1-acyl LPCMetaboliteCHEBI:17504 (ChEBI)
4xPALM-C-ABCA1 tetramerComplexR-HSA-5682067 (Reactome)
4xPALM-C-ABCA1 tetramerComplexR-HSA-5682073 (Reactome)
4xPALM-C-ABCA1 ProteinO95477 (Uniprot-TrEMBL)
4xPALM-C-p-2S-ABCA1 tetramer:APOA1ComplexR-HSA-5682094 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramerComplexR-HSA-5682107 (Reactome)
4xPALM-C-p-2S-ABCA1 ProteinO95477 (Uniprot-TrEMBL)
A2M ProteinP01023 (Uniprot-TrEMBL)
A2M tetramerComplexR-HSA-158255 (Reactome)
ABCA1 ProteinO95477 (Uniprot-TrEMBL)
ABCA1 tetramerComplexR-HSA-5682087 (Reactome)
ABCG1 ProteinP45844 (Uniprot-TrEMBL)
ABCG1 dimerComplexR-HSA-194222 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALB ProteinP02768 (Uniprot-TrEMBL)
ALBProteinP02768 (Uniprot-TrEMBL)
AMN ProteinQ9BXJ7 (Uniprot-TrEMBL)
ANGPTL3 ProteinQ9Y5C1 (Uniprot-TrEMBL)
ANGPTL3:ANGPTL8ComplexR-HSA-6784846 (Reactome)
ANGPTL3ProteinQ9Y5C1 (Uniprot-TrEMBL)
ANGPTL4ProteinQ9BY76 (Uniprot-TrEMBL)
ANGPTL8 ProteinQ6UXH0 (Uniprot-TrEMBL)
ANGPTL8ProteinQ6UXH0 (Uniprot-TrEMBL)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2(1-939) ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
APOA1(19-266)ProteinP02647 (Uniprot-TrEMBL)
APOA1(25-266) ProteinP02647 (Uniprot-TrEMBL)
APOA1(25-266)ProteinP02647 (Uniprot-TrEMBL)
APOA1(25-267) ProteinP02647 (Uniprot-TrEMBL)
APOA1(25-267)ProteinP02647 (Uniprot-TrEMBL)
APOA2(24-100) ProteinP02652 (Uniprot-TrEMBL)
APOA2(24-100)ProteinP02652 (Uniprot-TrEMBL)
APOA4 ProteinP06727 (Uniprot-TrEMBL)
APOA4 gene ProteinENSG00000110244 (Ensembl)
APOA4,APOA5,APOC2,CIDEC,FGF21 genesComplexR-HSA-6784668 (Reactome)
APOA4,APOA5,APOC2,CIDEC,FGF21ComplexR-HSA-6784718 (Reactome)
APOA4ProteinP06727 (Uniprot-TrEMBL)
APOA5 ProteinQ6Q788 (Uniprot-TrEMBL)
APOA5 gene ProteinENSG00000110243 (Ensembl)
APOA5ProteinQ6Q788 (Uniprot-TrEMBL)
APOB(28-2179) ProteinP04114 (Uniprot-TrEMBL)
APOB(28-2179)ProteinP04114 (Uniprot-TrEMBL)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
APOB(28-4563)ProteinP04114 (Uniprot-TrEMBL)
APOBR ProteinQ0VD83 (Uniprot-TrEMBL)
APOBR dimer:VLDLComplexR-HSA-8856140 (Reactome)
APOBR dimerComplexR-HSA-8854406 (Reactome)
APOC1 ProteinP02654 (Uniprot-TrEMBL)
APOC1ProteinP02654 (Uniprot-TrEMBL)
APOC2 ProteinP02655 (Uniprot-TrEMBL)
APOC2 gene ProteinENSG00000234906 (Ensembl)
APOC2ProteinP02655 (Uniprot-TrEMBL)
APOC3 ProteinP02656 (Uniprot-TrEMBL)
APOC3ProteinP02656 (Uniprot-TrEMBL)
APOC4 ProteinP55056 (Uniprot-TrEMBL)
APOC4ProteinP55056 (Uniprot-TrEMBL)
APOE ProteinP02649 (Uniprot-TrEMBL)
APOEProteinP02649 (Uniprot-TrEMBL)
APOFProteinQ13790 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
ApoB-48:TG:PL complexComplexR-HSA-174630 (Reactome)
ApoB-48:TG:PL complexComplexR-HSA-174756 (Reactome)
BMP1-3 ProteinP13497-3 (Uniprot-TrEMBL)
BMP1-3:Zn2+ComplexR-HSA-264759 (Reactome)
CES3ProteinQ6UWW8 (Uniprot-TrEMBL)
CETP ProteinP11597 (Uniprot-TrEMBL)
CETP:cholesterol ester complexComplexR-HSA-266340 (Reactome)
CETP:spherical

HDL:torcetrapib

complex
ComplexR-HSA-349410 (Reactome)
CETP:triacylglycerol complexComplexR-HSA-266351 (Reactome)
CHEST MetaboliteCHEBI:17002 (ChEBI)
CHESTMetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CHOLMetaboliteCHEBI:16113 (ChEBI)
CIDEC ProteinQ96AQ7-1 (Uniprot-TrEMBL)
CIDEC gene ProteinENSG00000187288 (Ensembl)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CLTC ProteinQ00610 (Uniprot-TrEMBL)
CREB3L3(1-?)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3(?-461)ProteinQ68CJ9 (Uniprot-TrEMBL)
CREB3L3ProteinQ68CJ9 (Uniprot-TrEMBL)
CUBN ProteinO60494 (Uniprot-TrEMBL)
CUBN:AMNComplexR-HSA-264830 (Reactome)
Clathrin:AP-2 complexComplexR-HSA-177505 (Reactome)
Clathrin:AP2 complexComplexR-HSA-2130671 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DAGsMetaboliteCHEBI:18035 (ChEBI)
FAMetaboliteCHEBI:35366 (ChEBI)
FAsMetaboliteCHEBI:35366 (ChEBI)
FGF21 ProteinQ9NSA1 (Uniprot-TrEMBL)
FGF21 gene ProteinENSG00000105550 (Ensembl)
FURIN ProteinP09958 (Uniprot-TrEMBL)
FURIN,PCSK6ComplexR-HSA-6784618 (Reactome)
GPIHBP1 ProteinQ8IV16 (Uniprot-TrEMBL)
GPIHBP1:HSPG:LPL dimerComplexR-HSA-8857969 (Reactome)
GPIHBP1ProteinQ8IV16 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDLBP ProteinQ00341 (Uniprot-TrEMBL)
HDLBP:HDLComplexR-HSA-8858255 (Reactome)
HDLBPProteinQ00341 (Uniprot-TrEMBL)
HSPG MetaboliteCHEBI:24499 (ChEBI)
HSPG:LPL dimerComplexR-HSA-8867477 (Reactome)
HSPGMetaboliteCHEBI:24499 (ChEBI)
Heparins MetaboliteCHEBI:24505 (ChEBI)
HeparinsMetaboliteCHEBI:24505 (ChEBI)
LCAT ProteinP04180 (Uniprot-TrEMBL)
LCAT:discoidal HDL complexComplexR-HSA-264684 (Reactome)
LCAT:spherical HDL complexComplexR-HSA-266308 (Reactome)
LCATProteinP04180 (Uniprot-TrEMBL)
LCFA(-)MetaboliteCHEBI:57560 (ChEBI)
LCFAsMetaboliteCHEBI:15904 (ChEBI)
LDL:LDLR complexComplexR-HSA-171056 (Reactome)
LDL:LDLR complexComplexR-HSA-171100 (Reactome)
LDL:LDLR complexComplexR-HSA-171108 (Reactome)
LDL:cholesterol ester complexComplexR-HSA-266339 (Reactome)
LDLR ProteinP01130 (Uniprot-TrEMBL)
LDLComplexR-HSA-171082 (Reactome) LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition.
LDLComplexR-HSA-171131 (Reactome) LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition.
LDLComplexR-HSA-8876367 (Reactome) LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition.
LDLRAP1ProteinQ5SW96 (Uniprot-TrEMBL)
LDLRProteinP01130 (Uniprot-TrEMBL)
LIPA-degraded LDLComplexR-HSA-8876365 (Reactome) LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition.
LIPAProteinP38571 (Uniprot-TrEMBL)
LIPC ProteinP11150 (Uniprot-TrEMBL)
LIPC dimer:LMF1,2ComplexR-HSA-6785173 (Reactome)
LIPC dimer:heparinComplexR-HSA-6785208 (Reactome)
LIPC dimerComplexR-HSA-6785179 (Reactome)
LIPC dimerComplexR-HSA-6785190 (Reactome)
LIPCProteinP11150 (Uniprot-TrEMBL)
LIPG ProteinQ9Y5X9 (Uniprot-TrEMBL)
LIPG dimerComplexR-HSA-6789313 (Reactome)
LMF1 ProteinQ96S06 (Uniprot-TrEMBL)
LMF1,2ComplexR-HSA-6785148 (Reactome)
LMF2 ProteinQ9BU23 (Uniprot-TrEMBL)
LPA ProteinP08519 (Uniprot-TrEMBL)
LPAProteinP08519 (Uniprot-TrEMBL)
LPL ProteinP06858 (Uniprot-TrEMBL)
LPL dimerComplexR-HSA-174592 (Reactome)
LPLProteinP06858 (Uniprot-TrEMBL)
LSR ProteinQ86X29 (Uniprot-TrEMBL)
LSR trimer:LDLComplexR-HSA-8933254 (Reactome)
LSR trimer:VLDLComplexR-HSA-8933291 (Reactome)
LSR trimerComplexR-HSA-8933252 (Reactome)
Lp(a)ComplexR-HSA-176866 (Reactome)
MBTPS1 ProteinQ14703 (Uniprot-TrEMBL)
MBTPS1,2ComplexR-HSA-6784711 (Reactome)
MBTPS2 ProteinO43462 (Uniprot-TrEMBL)
MTP:PDI:lipid complexComplexR-HSA-174681 (Reactome)
MTTP ProteinP55157 (Uniprot-TrEMBL)
MYLIP ProteinQ8WY64 (Uniprot-TrEMBL)
MYLIP dimerComplexR-HSA-8855129 (Reactome)
NCEH1ProteinQ6PIU2 (Uniprot-TrEMBL)
NPC1 ProteinO15118 (Uniprot-TrEMBL)
NPC1:CHOLComplexR-HSA-8876475 (Reactome)
NPC1ProteinO15118 (Uniprot-TrEMBL)
NPC2 ProteinP61916 (Uniprot-TrEMBL)
NPC2:CHOLComplexR-HSA-8876460 (Reactome)
NPC2ProteinP61916 (Uniprot-TrEMBL)
NR1H2 ProteinP55055 (Uniprot-TrEMBL)
NR1H2,NR1H3ComplexR-HSA-8854954 (Reactome)
NR1H3 ProteinQ13133 (Uniprot-TrEMBL)
P4HB ProteinP07237 (Uniprot-TrEMBL)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PCSK5ProteinQ92824 (Uniprot-TrEMBL)
PCSK6 ProteinP29122 (Uniprot-TrEMBL)
PCSK9 ProteinQ8NBP7 (Uniprot-TrEMBL)
PCSK9:LDLR:Clathrin:AP2ComplexR-HSA-6784728 (Reactome)
PCSK9:LDLR:Clathrin:AP2ComplexR-HSA-6784733 (Reactome)
PCSK9:LDLRComplexR-HSA-6784730 (Reactome)
PCSK9ProteinQ8NBP7 (Uniprot-TrEMBL)
PKA catalytic subunitComplexR-HSA-111920 (Reactome)
PL MetaboliteCHEBI:16247 (ChEBI)
PLMetaboliteCHEBI:16247 (ChEBI)
PLTP-1 ProteinP55058-1 (Uniprot-TrEMBL)
PLTP-2 ProteinP55058-2 (Uniprot-TrEMBL)
PLTPComplexR-HSA-194227 (Reactome)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SAR1BProteinQ9Y6B6 (Uniprot-TrEMBL)
SCARB1-2 ProteinQ8WTV0-2 (Uniprot-TrEMBL)
SCARB1-2ProteinQ8WTV0-2 (Uniprot-TrEMBL)
SOAT1 ProteinP35610 (Uniprot-TrEMBL)
SOAT1,2ComplexR-HSA-8876694 (Reactome)
SOAT2 ProteinO75908 (Uniprot-TrEMBL)
TAG MetaboliteCHEBI:17855 (ChEBI)
TAGMetaboliteCHEBI:17855 (ChEBI)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TAGsMetaboliteCHEBI:17855 (ChEBI)
TG-depleted chylomicronComplexR-HSA-174798 (Reactome)
Ub-K839-VLDLRProteinP98155 (Uniprot-TrEMBL)
VLDL (-APOC1,C4)ComplexR-HSA-8866325 (Reactome)
VLDL:PCSK9:Clathrin:AP2ComplexR-HSA-8855134 (Reactome)
VLDL:PCSK9:Clathrin:AP2ComplexR-HSA-8855135 (Reactome)
VLDL:PCSK9ComplexR-HSA-8855118 (Reactome)
VLDL:VLDLRComplexR-HSA-8854464 (Reactome)
VLDLR ProteinP98155 (Uniprot-TrEMBL)
VLDLComplexR-HSA-8855875 (Reactome)
VLDLComplexR-HSA-8866319 (Reactome)
VLDLRProteinP98155 (Uniprot-TrEMBL)
ZDHHC8ProteinQ9ULC8 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
acyl-CoAMetaboliteCHEBI:17984 (ChEBI)
albumin:2-lysophosphatidylcholine complexComplexR-HSA-264677 (Reactome)
apoA-I:CUBN:AMN complexComplexR-HSA-264851 (Reactome)
cholesterol MetaboliteCHEBI:16113 (ChEBI)
cholesterol esters MetaboliteCHEBI:17002 (ChEBI)
cholesterol estersMetaboliteCHEBI:17002 (ChEBI)
chylomicron

remnant:apoE

complex
ComplexR-HSA-174594 (Reactome)
chylomicron

remnant:apoE

complex
ComplexR-HSA-174792 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ComplexR-HSA-174658 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ComplexR-HSA-174749 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ComplexR-HSA-174816 (Reactome)
chylomicron remnantComplexR-HSA-174807 (Reactome)
chylomicronComplexR-HSA-174697 (Reactome)
discoidal HDL:cholesterolComplexR-HSA-266083 (Reactome)
discoidal HDLComplexR-HSA-216752 (Reactome)
enlarged spherical HDLComplexR-HSA-8855688 (Reactome)
nascent chylomicronComplexR-HSA-174626 (Reactome)
nascent chylomicronComplexR-HSA-174791 (Reactome)
phosphatidylcholinesMetaboliteCHEBI:16110 (ChEBI)
pre-VLDLComplexR-HSA-6784871 (Reactome)
pre-VLDLComplexR-HSA-8866311 (Reactome)
pre-beta HDLComplexR-HSA-349645 (Reactome)
spherical HDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-IIIComplexR-HSA-174769 (Reactome)
spherical HDL:apoC-II:apoC-III:apoEComplexR-HSA-174643 (Reactome)
spherical

HDL:triacylglycerol

complex
ComplexR-HSA-266348 (Reactome)
spherical HDL:SR-BI complexComplexR-HSA-349649 (Reactome)
spherical HDLComplexR-HSA-265523 (Reactome)
torcetrapib MetaboliteCHEBI:49203 (ChEBI)
torcetrapibMetaboliteCHEBI:49203 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
1-acyl LPCArrowR-HSA-264695 (Reactome)
1-acyl LPCR-HSA-264679 (Reactome)
4xPALM-C-ABCA1 tetramerArrowR-HSA-5682084 (Reactome)
4xPALM-C-ABCA1 tetramerArrowR-HSA-5682103 (Reactome)
4xPALM-C-ABCA1 tetramerR-HSA-5682101 (Reactome)
4xPALM-C-ABCA1 tetramerR-HSA-5682103 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramer:APOA1ArrowR-HSA-216727 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramer:APOA1mim-catalysisR-HSA-216723 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramer:APOA1mim-catalysisR-HSA-216757 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramerArrowR-HSA-5682101 (Reactome)
4xPALM-C-p-2S-ABCA1 tetramerR-HSA-216727 (Reactome)
A2M tetramerTBarR-HSA-264758 (Reactome)
ABCA1 tetramerR-HSA-5682084 (Reactome)
ABCG1 dimermim-catalysisR-HSA-266082 (Reactome)
ADPArrowR-HSA-216723 (Reactome)
ADPArrowR-HSA-216757 (Reactome)
ADPArrowR-HSA-266082 (Reactome)
ADPArrowR-HSA-5682101 (Reactome)
ALBR-HSA-264679 (Reactome)
ANGPTL3:ANGPTL8ArrowR-HSA-6784628 (Reactome)
ANGPTL3:ANGPTL8ArrowR-HSA-8856525 (Reactome)
ANGPTL3R-HSA-8856525 (Reactome)
ANGPTL4ArrowR-HSA-6784628 (Reactome)
ANGPTL4ArrowR-HSA-6784676 (Reactome)
ANGPTL8R-HSA-8856525 (Reactome)
APOA1(19-266)R-HSA-264758 (Reactome)
APOA1(25-266)ArrowR-HSA-264695 (Reactome)
APOA1(25-266)ArrowR-HSA-264758 (Reactome)
APOA1(25-266)R-HSA-216727 (Reactome)
APOA1(25-266)R-HSA-216756 (Reactome)
APOA1(25-266)R-HSA-264848 (Reactome)
APOA1(25-267)R-HSA-174741 (Reactome)
APOA2(24-100)R-HSA-174741 (Reactome)
APOA4,APOA5,APOC2,CIDEC,FGF21 genesR-HSA-6784622 (Reactome)
APOA4,APOA5,APOC2,CIDEC,FGF21ArrowR-HSA-6784622 (Reactome)
APOA4R-HSA-174741 (Reactome)
APOA5ArrowR-HSA-174757 (Reactome)
APOB(28-2179)R-HSA-174731 (Reactome)
APOB(28-2179)R-HSA-174786 (Reactome)
APOB(28-4563)R-HSA-8866329 (Reactome)
APOBR dimer:VLDLArrowR-HSA-8854408 (Reactome)
APOBR dimerR-HSA-8854408 (Reactome)
APOC1R-HSA-8866321 (Reactome)
APOC2ArrowR-HSA-174757 (Reactome)
APOC2R-HSA-266303 (Reactome)
APOC3R-HSA-266303 (Reactome)
APOC3TBarR-HSA-174757 (Reactome)
APOC4R-HSA-8866321 (Reactome)
APOER-HSA-174739 (Reactome)
APOER-HSA-266303 (Reactome)
APOFTBarR-HSA-266350 (Reactome)
ATPR-HSA-216723 (Reactome)
ATPR-HSA-216757 (Reactome)
ATPR-HSA-266082 (Reactome)
ATPR-HSA-5682101 (Reactome)
ApoB-48:TG:PL complexArrowR-HSA-174786 (Reactome)
ApoB-48:TG:PL complexR-HSA-174741 (Reactome)
BMP1-3:Zn2+mim-catalysisR-HSA-264758 (Reactome)
CES3mim-catalysisR-HSA-8937442 (Reactome)
CETP:cholesterol ester complexArrowR-HSA-266328 (Reactome)
CETP:cholesterol ester complexR-HSA-266350 (Reactome)
CETP:spherical

HDL:torcetrapib

complex
ArrowR-HSA-349404 (Reactome)
CETP:triacylglycerol complexArrowR-HSA-266350 (Reactome)
CETP:triacylglycerol complexR-HSA-266328 (Reactome)
CETP:triacylglycerol complexR-HSA-349404 (Reactome)
CHESTArrowR-HSA-264695 (Reactome)
CHESTArrowR-HSA-8876696 (Reactome)
CHESTArrowR-HSA-8876731 (Reactome)
CHESTR-HSA-174741 (Reactome)
CHESTR-HSA-6813720 (Reactome)
CHESTR-HSA-8866304 (Reactome)
CHESTR-HSA-8876731 (Reactome)
CHESTR-HSA-8937442 (Reactome)
CHOLArrowR-HSA-216723 (Reactome)
CHOLArrowR-HSA-266082 (Reactome)
CHOLArrowR-HSA-349638 (Reactome)
CHOLArrowR-HSA-6813720 (Reactome)
CHOLArrowR-HSA-8865667 (Reactome)
CHOLArrowR-HSA-8876485 (Reactome)
CHOLArrowR-HSA-8937442 (Reactome)
CHOLR-HSA-174741 (Reactome)
CHOLR-HSA-216723 (Reactome)
CHOLR-HSA-216756 (Reactome)
CHOLR-HSA-264695 (Reactome)
CHOLR-HSA-266082 (Reactome)
CHOLR-HSA-266089 (Reactome)
CHOLR-HSA-266299 (Reactome)
CHOLR-HSA-349657 (Reactome)
CHOLR-HSA-8866304 (Reactome)
CHOLR-HSA-8876472 (Reactome)
CHOLR-HSA-8876696 (Reactome)
CREB3L3(1-?)ArrowR-HSA-6784620 (Reactome)
CREB3L3(1-?)ArrowR-HSA-6784622 (Reactome)
CREB3L3(1-?)ArrowR-HSA-6784648 (Reactome)
CREB3L3(1-?)R-HSA-6784648 (Reactome)
CREB3L3(?-461)ArrowR-HSA-6784620 (Reactome)
CREB3L3R-HSA-6784620 (Reactome)
CUBN:AMNR-HSA-264848 (Reactome)
Clathrin:AP-2 complexR-HSA-6784735 (Reactome)
Clathrin:AP-2 complexR-HSA-8855131 (Reactome)
Clathrin:AP2 complexArrowR-HSA-6784738 (Reactome)
CoA-SHArrowR-HSA-5682084 (Reactome)
CoA-SHArrowR-HSA-8876696 (Reactome)
DAGsArrowR-HSA-174757 (Reactome)
DAGsArrowR-HSA-5694109 (Reactome)
DAGsArrowR-HSA-8980228 (Reactome)
FAArrowR-HSA-8865667 (Reactome)
FAsArrowR-HSA-5694109 (Reactome)
FURIN,PCSK6mim-catalysisR-HSA-6784628 (Reactome)
GPIHBP1:HSPG:LPL dimerArrowR-HSA-8857928 (Reactome)
GPIHBP1:HSPG:LPL dimerR-HSA-6784628 (Reactome)
GPIHBP1:HSPG:LPL dimerR-HSA-6784676 (Reactome)
GPIHBP1:HSPG:LPL dimermim-catalysisR-HSA-174757 (Reactome)
GPIHBP1ArrowR-HSA-6784628 (Reactome)
GPIHBP1ArrowR-HSA-6784676 (Reactome)
GPIHBP1R-HSA-8857928 (Reactome)
H2OR-HSA-216723 (Reactome)
H2OR-HSA-216757 (Reactome)
H2OR-HSA-266082 (Reactome)
H2OR-HSA-5694109 (Reactome)
H2OR-HSA-6813720 (Reactome)
H2OR-HSA-8865667 (Reactome)
H2OR-HSA-8937442 (Reactome)
H2OR-HSA-8980228 (Reactome)
HDLBP:HDLArrowR-HSA-8858252 (Reactome)
HDLBPR-HSA-8858252 (Reactome)
HSPG:LPL dimerArrowR-HSA-6784861 (Reactome)
HSPG:LPL dimerR-HSA-8857928 (Reactome)
HSPGArrowR-HSA-6784628 (Reactome)
HSPGArrowR-HSA-6784676 (Reactome)
HSPGR-HSA-6784861 (Reactome)
HeparinsR-HSA-6785213 (Reactome)
LCAT:discoidal HDL complexArrowR-HSA-264678 (Reactome)
LCAT:discoidal HDL complexR-HSA-264689 (Reactome)
LCAT:spherical HDL complexArrowR-HSA-266315 (Reactome)
LCAT:spherical HDL complexR-HSA-266310 (Reactome)
LCATArrowR-HSA-264689 (Reactome)
LCATArrowR-HSA-266310 (Reactome)
LCATR-HSA-264678 (Reactome)
LCATR-HSA-266315 (Reactome)
LCATmim-catalysisR-HSA-264695 (Reactome)
LCFA(-)ArrowR-HSA-6813720 (Reactome)
LCFA(-)ArrowR-HSA-8937442 (Reactome)
LCFAsArrowR-HSA-174757 (Reactome)
LCFAsArrowR-HSA-8980228 (Reactome)
LDL:LDLR complexArrowR-HSA-171059 (Reactome)
LDL:LDLR complexArrowR-HSA-171122 (Reactome)
LDL:LDLR complexArrowR-HSA-171141 (Reactome)
LDL:LDLR complexR-HSA-171059 (Reactome)
LDL:LDLR complexR-HSA-171106 (Reactome)
LDL:LDLR complexR-HSA-171141 (Reactome)
LDL:cholesterol ester complexArrowR-HSA-266350 (Reactome)
LDLArrowR-HSA-171106 (Reactome)
LDLArrowR-HSA-8876366 (Reactome)
LDLR-HSA-171122 (Reactome)
LDLR-HSA-176879 (Reactome)
LDLR-HSA-266350 (Reactome)
LDLR-HSA-8865667 (Reactome)
LDLR-HSA-8876366 (Reactome)
LDLR-HSA-8933258 (Reactome)
LDLRAP1ArrowR-HSA-171141 (Reactome)
LDLRAP1ArrowR-HSA-174706 (Reactome)
LDLRArrowR-HSA-171087 (Reactome)
LDLRArrowR-HSA-171106 (Reactome)
LDLRArrowR-HSA-174624 (Reactome)
LDLRR-HSA-171087 (Reactome)
LDLRR-HSA-171122 (Reactome)
LDLRR-HSA-174657 (Reactome)
LDLRR-HSA-6784734 (Reactome)
LIPA-degraded LDLArrowR-HSA-8865667 (Reactome)
LIPAmim-catalysisR-HSA-8865667 (Reactome)
LIPC dimer:LMF1,2ArrowR-HSA-6785181 (Reactome)
LIPC dimer:LMF1,2R-HSA-6785178 (Reactome)
LIPC dimer:heparinArrowR-HSA-6785213 (Reactome)
LIPC dimer:heparinmim-catalysisR-HSA-5694109 (Reactome)
LIPC dimerArrowR-HSA-6785178 (Reactome)
LIPC dimerR-HSA-6785181 (Reactome)
LIPC dimerR-HSA-6785213 (Reactome)
LIPCArrowR-HSA-174657 (Reactome)
LIPG dimermim-catalysisR-HSA-8980228 (Reactome)
LMF1,2ArrowR-HSA-6785178 (Reactome)
LMF1,2R-HSA-6785181 (Reactome)
LPAR-HSA-176879 (Reactome)
LPL dimerR-HSA-6784861 (Reactome)
LPLArrowR-HSA-6784628 (Reactome)
LPLArrowR-HSA-6784676 (Reactome)
LSR trimer:LDLArrowR-HSA-8933258 (Reactome)
LSR trimer:VLDLArrowR-HSA-8933292 (Reactome)
LSR trimerR-HSA-8933258 (Reactome)
LSR trimerR-HSA-8933292 (Reactome)
Lp(a)ArrowR-HSA-176879 (Reactome)
MBTPS1,2mim-catalysisR-HSA-6784620 (Reactome)
MTP:PDI:lipid complexArrowR-HSA-174741 (Reactome)
MTP:PDI:lipid complexmim-catalysisR-HSA-174786 (Reactome)
MTP:PDI:lipid complexmim-catalysisR-HSA-8866329 (Reactome)
MYLIP dimermim-catalysisR-HSA-8854628 (Reactome)
NCEH1mim-catalysisR-HSA-6813720 (Reactome)
NPC1:CHOLArrowR-HSA-8876484 (Reactome)
NPC1:CHOLR-HSA-8876485 (Reactome)
NPC1ArrowR-HSA-8876485 (Reactome)
NPC1R-HSA-8876484 (Reactome)
NPC2:CHOLArrowR-HSA-8876472 (Reactome)
NPC2:CHOLR-HSA-8876484 (Reactome)
NPC2ArrowR-HSA-8876484 (Reactome)
NPC2R-HSA-8876472 (Reactome)
NR1H2,NR1H3ArrowR-HSA-8854628 (Reactome)
PALM-CoAR-HSA-5682084 (Reactome)
PCSK5mim-catalysisR-HSA-6784676 (Reactome)
PCSK9:LDLR:Clathrin:AP2ArrowR-HSA-6784729 (Reactome)
PCSK9:LDLR:Clathrin:AP2ArrowR-HSA-6784735 (Reactome)
PCSK9:LDLR:Clathrin:AP2R-HSA-6784729 (Reactome)
PCSK9:LDLR:Clathrin:AP2R-HSA-6784738 (Reactome)
PCSK9:LDLRArrowR-HSA-6784734 (Reactome)
PCSK9:LDLRR-HSA-6784735 (Reactome)
PCSK9R-HSA-6784734 (Reactome)
PCSK9R-HSA-8855111 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-5682101 (Reactome)
PLArrowR-HSA-216757 (Reactome)
PLArrowR-HSA-349638 (Reactome)
PLR-HSA-174786 (Reactome)
PLR-HSA-216756 (Reactome)
PLR-HSA-216757 (Reactome)
PLR-HSA-266299 (Reactome)
PLR-HSA-349657 (Reactome)
PLR-HSA-8866304 (Reactome)
PLR-HSA-8866329 (Reactome)
PLTPArrowR-HSA-266299 (Reactome)
PiArrowR-HSA-216723 (Reactome)
PiArrowR-HSA-216757 (Reactome)
PiArrowR-HSA-266082 (Reactome)
R-HSA-171059 (Reactome) LDL:LDLR complexes move rapidly from clathrin-coated vesicles to endosomes (Goldstein et al. 1979).
R-HSA-171087 (Reactome) LDL receptors in the endosome membrane are quickly returned to the cell surface (Goldstein et al. 1979).
R-HSA-171106 (Reactome) Dissociation of the LDL:LDLR complex in the early endosome frees the LDL particle to be transferred to lysosomes for degradation while the LDL receptor is returned to the plasma membrane (Goldstein et al. 1979).
R-HSA-171122 (Reactome) Low density lipoprotein (LDL) particles associate with LDL receptors (LDLR) at the cell surface (Goldstein et al. 1979). This binding is mediated by the apoprotein B-100 component of the LDL particle, which binds LDLR with 1:1 stoichiometry (van Driel et al. 1989).
R-HSA-171141 (Reactome) Low density lipoprotein (LDL) particles bound to their receptors (LDLR) in coated pits on the cell surface are taken up into clathrin-coated vesicles (Goldstein et al. 1979). In hepatocytes and lymphocytes, but not in fibroblasts, this process requires the presence of an additional protein, LDLRAP1 (ARH1). In human patients, LDLRAP1 deficiency is associated with hypercholesterolemia, emphasizing the central role of the liver in clearance of circulating LDL in vivo (Eden et al. 2002; Garuti et al. 2005; He et al. 2002; Michaely et al. 2004). In vitro, LDLRAP1 protein binds both to LDLR and to components of the clathrin coat, suggesting that it might play an essential bridging function during the movement of LDL:LDLR complexes into clathrin-coated vesicles. This role has not yet been demonstrated in vivo, however, nor is it clear what might substitute for such a bridging function in fibroblasts.
R-HSA-174587 (Reactome) While the export pathway for nascent chylomicrons has not been directly characterized in human cells, the requirement for SAR1B protein for normal chylomicron export in vivo (Jones et al. 2003) indicates that nascent chylomicrons are exported from the endoplasmic reticulum via the Golgi apparatus in COPII vesicles.
R-HSA-174624 (Reactome) The molecular details of this event are inferred from the dissociation of the LDL:LDLR complex in the endosome.
R-HSA-174657 (Reactome) Chylomicron micron remnants containing apolipoprotein E associate with the surfaces of cells in a process that probably involves several steps and that requires the presence (but not the catalytic activity) of heparan sulfate proteoglycan (HSPG)-associated hepatic lipase (HL). This process ultimately results in binding of the remnant to cell-surface LDL receptors (LDLR) (Ji et al. 1994). The molecular details of LDLR binding, and of the following steps of remnant endocytosis, are inferred from those of the coorresponding step of LDLR-mediated low-density lipoprotein (LDL) endocytosis. In the body, this process occurs in the liver.
R-HSA-174660 (Reactome) Circulating nascent chylomicrons acquire copies of apolipoproteins C-II, C-III, and E from circulating spherical (mature) high-density lipoprotein particles, becoming mature chylomicrons (Havel et al. 1973; Bisgaier and Glickman 1983). Here, this interaction is annotated to involve the transfer of a single copy of each lipoprotein, but a mature chylomicron in fact contains approximately 25 copies of apolipoprotein E and 180 copies of C apolipoproteins (Bhattacharya and Redgrave 1981).
R-HSA-174690 (Reactome) Triacylglycerol (TG)-depleted chylomicrons transfer A and C apoproteins to spherical (mature) HDL, generating chylomicron remnants (Havel and Kane 2001). This transfer is arbitrarily annotated here as involving one molecule of each apolipoprotein. The molecular difference that enables nascent chylomicrons to accept apolipoproteins from sperical HDL and TG-depleted chylomicrons to donate them is unclear.
R-HSA-174706 (Reactome) The molecular details of this event are inferred from those of LDLR-mediated low-density lipoprotein (LDL) endocytosis into coated vesicles (Ji et al. 1994).
R-HSA-174731 (Reactome) Newly synthesized apoB-48 that is not complexed with lipid is rapidly degraded (Dixon et al. 1991). The mechanism and site of this degradation (within the endoplasmic reticulum or in cytosolic proteasomes) is unclear.
R-HSA-174739 (Reactome) In the body, this binding involved apoE synthesized by hepatocytes and concentrated in the space of Disse, an extracellular compartment adjacent to the hepatocytes to which blood-borne lipoprotein particles have free access (Ji et al. 1994).
R-HSA-174741 (Reactome) The second phase of chylomicron assembly takes place in the lumen of the endoplasmic reticulum. ApoB-48 continues to bind triacylglycerol, as well as cholesterol, cholesterol esters, and molecules of apolipoproteins A-I, A-II, and A-IV. The reaction is annotated here to involve small numbers of these molecules, but the true numbers in vivo are much greater - a nascent chylomicron entering the lymphatic circulation contains >200,000 molecules of triacylglycerol (TG), ~35,000 of phospholipid, ~11,000 of cholesterol ester, ~8,000 of free cholesterol, ~60 copies of apolipoprotein A-I, ~15 copies of apolipoprotein A-IV, and copies of apolipoprotein A-II (Bhattacharya and Redgrave 1981; Havel and Kane 2001).

The presence of MTP:PDI (microsomal triacylglycerol transfer protein:protein disulfide isomerase) is required for lipid addition both in vitro and in vivo, but its molecular role at this stage of chylomicron formation is unclear and may be indirect (Gordon et al. 1995; Hussain et al. 2003).

R-HSA-174757 (Reactome) Lipoprotein lipase dimers (LPL:LPL) are tethered to heparan sulfate proteoglycans (HSPG) at endothelial cell surfaces (Fernandez-Borja et al. 1996; Peterson et al. 1992). Both syndecan 1 (Rosenberg et al. 1997) and perlecan (Goldberg 1996) HSPG molecules are capable of tethering LPL. The LPL enzyme catalyzes the hydrolysis and release of triacylglycerols (TG) associated with circulating chylomicrons to leave a CM remnant (CR). This reaction is annotated here as causing the hydrolysis and release of 50 molecules of TG. In vivo, the number is much larger, and TG depletion probably occurs in the course of multiple encounters between a chylomicron and endothelial LPL. This reaction is strongly activated by chylomicron-associated apo C-II protein both in vivo and in vitro (Jackson et al. 1986). Chylomicron-associated apoC-II protein inhibits LPL activity in vitro (Brown and Baginsky 1972), and recent studies have indicated a positive regulatory role for apoA-5 protein, though its molecular mechanism of action remains unclear (Marcais et al. 2005; Merkel and Heeren 2005). CRs can then be taken up by liver parenchymal cells in two ways; 1) directly by the LDL receptor or 2) apoE/HSPG-directed uptake by LDL receptor-related proteins.
R-HSA-174786 (Reactome) Phospholipid (PL) and triacylglycerol (TG) associate with the apo B-48 polypeptide as it is translated. This process is mediated by MTP (microsomal triacylglycerol transfer protein) in the form of a MTP:PDI (protein disulfide isomerase) heterodimer. MTP in vitro binds small amounts of PL and TG (annotated here as as one molecule of each) and efficiently transfers the bound lipid between membranes (Atzel and Wetterau 1994). In vivo, MTP:PDI directly interacts with apoB-48 polypeptide (Wu et al. 1996), and is thought to transfer lipid from the endoplasmic reticulum membrane to nascent apoB-48. While some of the molecular details of MTP function remain unclear, this function is clearly essential in vivo, as patients who lack MTP cannot produce chylomicrons (e.g., Wetterau et al. 1992; Narcisi et al. 1995).
R-HSA-174808 (Reactome) The molecular details of this event are inferred from those of LDLR-mediated low-density lipoprotein (LDL) transport from coated vesicles to endosomes.
R-HSA-176879 (Reactome) As an alternative to LDLR-mediated uptake and degradation, a LDL particle can bind a single molecule of LPA (apolipoprotein A), forming a Lp(a) lipoprotein particle. Although LPA is synthesized in liver cells, LPA - LDL binding appears to occur primarily extracellularly in vivo, on the hepatocyte surface or in the blood (Lobentanz et al. 1998). Lp(a) particles are relatively long-lived, with a half-life in human plasma of three to four days (Krempler et al. 1980), and the molecular mechanism of their clearance from the blood in vivo remains obscure. Lp(a) particles are of clinical interest because elevated levels of them are correlated with elevated risk of coronary heart disease (reviewed by Marcovina et al. 2003).
R-HSA-216723 (Reactome) In an ATP-dependent reaction, ATP-binding cassette sub-family A member 1 (ABCA1, ATPA1) mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. Cholesterol associated with cytosolic vesicles is a substrate for this reaction. Under physiologocal conditions, the active form of ABCA1 is predominantly a tetramer associated with apolipoprotein A-I (APOA1) (Denis et al. 2004; Vedhachalam et al., 2007). The number of lipid molecules transported per ATP consumed is not known.
R-HSA-216727 (Reactome) ABCA1 associated with the plasma membrane binds extracellular apolipoprotein A-I (APOA1), forming a membrane-associated complex. The predominant form of ABCA1 is a heterotetramer (Denis et al. 2004), although studies in model systems in vitro are consistent with the hypothesis that the protein may also occur as a dimer (Trompier et al. 2006).
R-HSA-216756 (Reactome) Extracellular apolipoprotein A-I interacts with phospholipid- and cholesterol-rich membrane patches formed through the action of ABCA1, binding these two lipids to form a discoidal (small nascent) HDL particle (HDL 3c - Kontush and Chapman 2006). The apoA-I molecules that accept lipids in this reaction appear to be different from the ones that activate ABCA1 at the plasma membrane (Hassan et al. 2007; Vedhachalam et al. 2007).
R-HSA-216757 (Reactome) In an ATP-dependent reaction, ATPA1 mediates the movement of intracellular phospholipid to the extracellular face of the plasma membrane. Cholesterol associated with cytosolic vesicles is a substrate for this reaction. Under physiologocal conditions, the active form of ABCA1 is predominantly a tetramer associated with apolipoprotein A-I (APOA1) (Denis et al. 2004, Vedhachalam et al. 2007). The number of lipid molecules transported per ATP consumed is not known.
R-HSA-264678 (Reactome) LCAT (lecithin-cholesterol acyltransferase) associates strongly but reversibly with discoidal HDL particles (Jonas 2000).
R-HSA-264679 (Reactome) Serum albumin binds 2-lysophosphatidylcholine (lysolecithin) to form a complex. Two molecules of lipid bind strongly to a molecule of albumin; an additional five molecules bind more weakly (Nakagawa and Nishida 1973). The fate of the complex in vivo is unclear. In vitro 2-lysophosphatidylcholine can be esterified with fatty acid to generate phosphatidylcholine. Such a process could replenish the phosphatidylcholine consumed by cholesterol esterification in HDL particles, but the extent to which it occurs in vivo is unclear (Nakagawa and Nishida 1973; Switzer and Eder 1965).
R-HSA-264689 (Reactome) The LCAT:discoidal HDL complex dissociates reversibly to yield LCAT and a discoidal HDL particle.
R-HSA-264695 (Reactome) LCAT activated by apoA-I catalyzes the reaction of cholesterol and phosphatidylcholine to yield cholesterol esterified with a long-chain fatty acid and 2-lysophosphatidylcholine. While this reaction was first studied in vitro using purified proteins in solution, it occurs in vivo on the surfaces of HDL particles where transiently-bound LCAT is activated by HDL-associated apoA-I protein and consumes HDL-associated cholesterol and phosphatidylcholine. The cholesterol ester reaction product is strongly associated with the HDL particle because of its increased hydrophobicity, while the 2-lysophosphatidylcholine product is released from the particle (Fielding et al. 1972 [2 references]; Adimoolam et al. 1998).
R-HSA-264758 (Reactome) The six aminoterminal residues of pro-apolipoprotein A-1 are removed to generate the mature, lipid-binding form of the protein (APOA1). Studies of tissue culture systems suggest that BMP1 catalyzes this reaction (Chau et al. 2006, 2007). While BMP1 is annotated here as a monomer, its subunit structure is not known, and its 1:1 association with Zn2+ is inferred from its sequence similarity to known metallopeptidases. Tetrameric alpha2-macroglobulin (A2M) at concentrations found in plasma in inflammatory responses inhibits this reaction in vitro, suggesting a possible link between inflammation and perturbation of HDL function (Zhang et al. 2006, Chau et al. 2007).
R-HSA-264834 (Reactome) ApoA-I bound to CUBN:AMN on the cell surface is endocytosed, moved to lysosomes, and degraded (Kozyraki et al. 1999). It is not known whether the CUBN:AMN complex is also degraded or recycled to the cell surface.
R-HSA-264848 (Reactome) Extracellular apoA-I protein binds to the CUBN (cubilin) subunit of the CUBN:AMN complex associated with the plasma membrane. In the body, this complex is found on the apical surfaces of kidney glomerular cells, where it mediates binding and endocytosis of proteins in the glomerular filtrate, and on the apical surfaces of enterocytes, where it mediates uptake of several vitamins complexed with carrier proteins (notably vitamin B12 (cobalamin):intrinsic factor) (Kozyraki et al. 1999; Fyfe et al. 2004).
R-HSA-266082 (Reactome) In an ATP-dependent reaction, ABCG1 mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. In a tissue culture model system, the active form of ABCG1 is predominantly a tetramer (Vuaghan and Oram 2005). The number of lipid molecules transported per ATP consumed is not known.
R-HSA-266089 (Reactome) Extracellular discoidal HDL particles interact with cholesterol-rich membrane patches formed through the action of ABCG1 (Vaughan and Oram 2005). In the body this reaction is a key step in the process of reverse cholesterol transport, by which excess cholesterol is recovered from cells such a macrophages and transported ultimately to the liver. At a molecular level, it is one of the steps in the transformation of discoidal (small nascent) HDL particles into spherical ones, distinct from the similar reaction in which cholesterol is transferred to lipid-free apoA-I protein (Oram and Vaughan 2006; Kontush and Chapman 2006).
R-HSA-266299 (Reactome) Spherical (mature) HDL particles can acquire additional molecules of free cholesterol (CHOL) and phospholipid (PL) from cell membranes. In the body, this is an important step in the so-called reverse cholesterol transport process in which excess CHOLl, notably in foam cells in atherosclerotic plaques, is transferred to HDL particles and transported ultimately to the liver. While studies in vitro and in mutant mice indicate that PLTP (phospholipid transfer protein) plays a major role in this process, its molecular details remain unclear (Oram et al. 2003) and the reaction is annotated here as the addition of two molecules each of CHOL and PL to a spherical HDL to create an "enlarged" spherical HDL.
R-HSA-266303 (Reactome) Spherical HDL particles can bind apoC-II, apoC-III and and apoE proteins. The sources of these proteins and their role or roles in HDL function under physiological conditions are not well understood, however (Kontush and Chapman 2006).
R-HSA-266310 (Reactome) The LCAT:spherical HDL complex dissociates reversibly to yield LCAT and a spherical HDL particle.
R-HSA-266315 (Reactome) LCAT (lecithin-cholesterol acyltransferase) associates strongly but reversibly with spherical HDL particles (Jonas 2000).
R-HSA-266328 (Reactome) CETP (cholesterol ester transfer protein) complexed with triacylglycerol interacts with a spherical HDL (high density lipoprotein) particle, acquiring cholesterol ester molecules and donating triacylglycerol to the HDL (Swenson et al. 1988; Morton and Zilversmit 1983). This process is reversible but in the body proceeds in the direction annotated here. A model for the lipid exchange process has been proposed based on recent studies of the structure of CETP:lipid complexes (Qiu et al. 2007).
R-HSA-266350 (Reactome) CETP (cholesterol ester transfer protein) complexed with cholesterol esters interacts with an LDL (low density lipoprotein) particle, acquiring triacylglycerol molecules and donating cholesterol ester to the LDL (Swenson et al. 1988; Morton and Zilversmit 1983). This process is reversible but in the body proceeds in the direction annotated here. A model for the lipid exchange process has been proposed based on recent studies of the structure of CETP:lipid complexes (Qiu et al. 2007).

Apolipoprotein F (APOF) can be associated with HDLs and LDLs. It can inhibit cholesteryl ester transfer protein (CETP) activity, thus inhibiting CETP-mediated transfer events specifically involving the LDL particle (Wang et al. 1999). The function of HDL-associated APOF, which represents >75% of the total plasma pool, is currently unknown. Although over-expression of mouse ApoF can accelerate plasma clearance of HDL (Lagor et al. 2009), physiological levels of ApoF do not affect HDL clearance (Lagor et al. 2012).

Apolipoprotein C-I (APOC1) is an Inhibitor of lipoproteins binding to their respective low density lipoprotein LDL receptor (LDLR), LDL receptor-related protein, and very low density lipoprotein receptor (VLDLR). It directly binds circulating fatty acids therby inhibiting their cellular uptake and is also the major plasma inhibitor of CETP (Westerterp et al. 2007).
R-HSA-349404 (Reactome) Torcetrapib associates with a molecule of CETP and a spherical HDL particle to form a stable complex, thus trapping CETP and inhibiting CETP-mediated lipid transfer between HDL and LDL (Clark et al. 2006).
R-HSA-349637 (Reactome) An extracellular spherical HDL particle binds to the plasma membrance-associated SR-BI receptor with high affinity (Murao et al. 1997). In the body SR-BI receptors are abundant on the surfaces of steroidogenic cells in the adrenal glands and gonads, and on hepatocytes. SR-BI thus appears to play a central role in cholesterol uptake for steroid hormone synthesis and for bile acid synthesis and cholesterol excretion (Rigotti et al. 2003; Silver and Tall 2001).
R-HSA-349638 (Reactome) Spherical HDL particles bound to the cell-surface SR-BI receptor are disassembled, with the release of pre-beta HDL (essentially apoA-I lipoprotein with a few molecules of bound lipid) and the cellular uptake of the bulk of the HDL-associated cholesterol, cholesterol esters, phospholipids, and triacylglycerols. The specificity and efficiency of this process has been demonstrated through a variety of studies in tissue culture model systems (Rigotti et al. 2003; Silver and Tall 2001). The process is annotated here as a concerted event occuring at the cell surface but its molecular details remain incompletely defined and it is possible that the HDL particle is internalized while undergoing disassembly.
R-HSA-349657 (Reactome) Pre-beta HDL (lipid-poor apoA-I) interacts with phospholipid- and cholesterol-rich membrane patches formed through the action of ABCA1, binding these two lipids to form a discoidal (small nascent) HDL particle (HDL 3c - Kontush and Chapman 2006).
R-HSA-5682084 (Reactome) Palmitoylation of ATP-binding cassette sub-family A member 1 (ABCA1) at Cys 3, 23, 1110 and 1111 is essential for its proper trafficking from the ER membrane to the plasma membrane where it is essential for the transport of lipids. The probable palmitoyltransferase ZDHHC8 mediates the palmitoylation of ABCA1 (Singaraja et al. 2009).
R-HSA-5682101 (Reactome) ATP-binding cassette sub-family A member 1 (ABCA1) is a key mediator of cholesterol and phospholipid efflux to apolipoprotein particles. This efflux activity is regulated by protein kinase A (PKA) site-specific phosphorylation of ABCA1 at Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1 (See et al. 2002).
R-HSA-5682103 (Reactome) Palmitoylation of ATP-binding cassette sub-family A member 1 (ABCA1) at Cys 3, 23, 1110 and 1111 is essential for its proper trafficking from the ER membrane to the plasma membrane where it is essential for the transport of lipids (Singaraja et al. 2009).
R-HSA-5694109 (Reactome) Fatty acids (FAs) are used as energy substrates and are stored as triglycerides. Triacylglycerol (TAG) has to be cleaved by lipases to be able to move in and out of cells for usage. Hepatic triacylglycerol lipase (LIPC) is one of several enzymes that catalyses the hydrolysis of TAGs to free fatty acids (FAs) and diacylglycerol (DAG) (Hegele et al. 1993, Santamarina-Fojo et al. 2004). Defects in LIPC can cause hepatic lipase deficiency (HL deficiency; MIM:614025), a disorder characterised by premature atherosclerosis and abnormal circulating lipoproteins (Hegele et al. 1992, 1993).
R-HSA-6784620 (Reactome) Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3) is a transcription factor that is highly and selectively expressed in liver and small intestine. This protein is produced as an ER-localized type II transmembrane glycoprotein that is converted into the mature nuclear form (the N-terminal portion) by sequence specific proteases, membrane-bound transcription factor site-1 proteases 1 and 2 (MBTPS1 and 2) (Marschner et al. 2011, Oeffner et al. 2009). CREB3L3 is a downstream target gene of hepatocyte nuclear factor 4a (HNF-4a), which plays a critical role in hepatocyte differentiation and liver function. Ablation of HNF-4a abolished CREB-H mRNA expression in the liver, but not in the small intestine, suggesting an essential role of HNF-4a in hepatic CREB-H expression.
R-HSA-6784622 (Reactome) Crebh(1-?) enters the nucleoplasm and induces the expression of APOA4, APOA5, APOC2, CIDEC and FGF21 (Lee et al. 2011). APOA4, APOA5 and APOC2 are known to augment lipoprotein lipase (LPL) activity. LPL is bound to the vascular endothelium, and hydrolyzes chylomicron and VLDL- associated TG to facilitate the transport of hydrolyzed fatty acids to peripheral cells. Patients with genetic defects in AOPC2, APOA5 or LPL display high circulating TG levels due to impaired TG clearance. Identification of APOA4, APOA5 and APOC2 as CREB-H target genes suggests that CREB-H might be involved in TG catabolism. CREB-H also strongly induces FGF21, a liver expressed hormone that has antidiabetic and TG- lowering effects, and CIDEC which encodes a lipid droplet-associated protein (Lee 2012).
R-HSA-6784628 (Reactome) LPL enzyme is catalytically active as a dimer composed of two glycosylated subunits of LPL connected in a head-to-tail arrangement by non-covalent interactions. Dimeric LPL is cleaved by several proprotein convertases. FURIN and proprotein convertase subtilisin/kexin type 6 (PCSK6 aka PACE4) can cleave LPL dimer, inactivating it, resulting in subsequent increase in plasma TG concentrations (Siezen et al. 1994, Bassi et al. 2000, Jin et al. 2005). Endogenous modulators of LPL are the angiopoietin-like proteins ANGPTL3 and ANGPTL4, which can bind transiently to LPL dimer, resulting in conversion of the enzyme from a catalytically active dimer to inactive, but still folded, monomers (Liu et al. 2010, Sukonina et al. 2006). ANGPTL4 regulates plasma triglyceride concentration via the inhibition of LPL (Dijk & Kersten 2014). GWAS studies (Dewey et al. 2016, MIG and CARDIoGRAM Consortium 2016) show a strong correlation between inactivating ANGPTL4 mutants and lower levels of triglycerides and lower risk of coronary artery disease than non-carriers. Therapeutic modulation of ANGPTL4 could be a new strategy against dyslipidemia (Kersten 2016).
R-HSA-6784648 (Reactome) The N-terminal fragment of CREB3L3 is released to the cytosol and translocates to the nucleus (Chan et al. 2010, Chin et al. 2005) to induce the transcriptional activation of different genes such as Apoa4, Apoa5, and Apoc2 apolipoproteins which exhibit stimulatory effects on lipoprotein lipase (LPL). Consistent with the essential role of LPL in TG clearance, CREB3L3-deficient mice showed hypertriglyceridemia, associated with defective production of these apolipoproteins and decreased LPL activity.
R-HSA-6784676 (Reactome) LPL enzyme is catalytically active as a dimer composed of two glycosylated subunits of LPL connected in a head-to-tail arrangement by non-covalent interactions. Dimeric LPL is cleaved by several proprotein convertases. Proprotein convertase subtilisin/kexin type 5 (PCSK5) can cleave LPL dimer, inactivating it, resulting in subsequent increase in plasma TG concentrations (Paule et al. 2012). ANGPTL4 binds transiently to LPL dimer, the interaction resulting in conversion of the enzyme from a catalytically active dimer to inactive, but still folded, monomers (Sukonina et al. 2006).
R-HSA-6784729 (Reactome) The PCSK9:LDLR:Clathrin-coated vesicle is internalized to endosomes and, after that, to lysosomes where PCSK9 and LDLR are degraded (Wang et al. 2012).
R-HSA-6784734 (Reactome) PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds to LDLR (Low-density lipoprotein receptor) on the cell surface. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR (Zhang et al. 2007). The complex PCSK9:LDLR is internalized via clathrin-mediated endocytosis and then routed to lysosomes via a mechanism that does not require ubiquitination and is distinct from the autophagy and proteosomal degradation pathways. In lysosomes, the affinity of the interaction between PCSK9 and LDLR dramatically increases. This promotes the final degradation of PCSK9 and LDLR without recycling. Monoclonal antibodies targeting PCSK9 have been shown to markedly reduce LDL cholesterol levels and are a novel treatment strategy for adults with hypercholesterolemia (Navarese et al. 2015).
R-HSA-6784735 (Reactome) LDLR that engage PCSK9 at the cell membrane are internalized via the canonical clathrin-dependent endocytic machinery (Wang et al. 2012). This complex is routed to lysosomes via a pathway that does not require ubiquitination of the cytoplasmic tail of the receptor and does not involve the proteasomal or autophagy pathways. The clathrin is required for the internalization of the LDLR-PCSK9 complex that forms on the cell surface.
R-HSA-6784738 (Reactome) LDLR that engage PCSK9 at the cell membrane are internalized via the canonical clathrin-dependent endocytic machinery (Wang et al. 2012). This complex is routed to lysosomes via a pathway that does not require ubiquitination of the cytoplasmic tail of the receptor and does not involve the proteasomal or autophagy pathways. The clathrin is required for the internalization of the LDLR-PCSK9 complex that forms on the cell surface.
R-HSA-6784861 (Reactome) LPL enzyme is catalytically active as a dimer composed of two glycosylated subunits of LPL connected in a head-to-tail arrangement by non-covalent interactions. It is synthesised in adipocytes and exported to the luminal side of the capillary endothelium where it binds heparan sulfate proteoglycan (HSPG), serving as an membrane anchor for the LPL dimer (Lookene et al. 1997, Berryman & Bensadoun 1995).
R-HSA-6785178 (Reactome) Hepatic triacylglycerol lipase (LIPC, and lipoprotein lipase, LPL) are dimeric lipases (Hill et al. 1997) that hydrolyse triglycerides from circulating lipoproteins thereby playing important roles in lipoprotein remodeling and uptake. LIPC dimer (as well as LPL dimer) binds to an ER membrane protein known as lipase maturation factor 1 (LMF1) which can mediate secretion and enzymatic maturation of these lipases. Human LMF1 contain five TM segments that divide the protein into six separate domains with cytoplasmic and ER lumenal orientation thereby transporting LIPC dimer from ER lumen to the cytosol. The mechanism of LIPC dimer translocation from cytosol to secretion is unknown (Doolittle et al. 2009, Babilonia-Rosa & Neher 2014). Another family member, LMF2, may function as LMF1 based on similarity. Defects in LMF1 can cause combined lipase deficiency (CLD; MIM:246650), characterised by hypertriglyceridemia caused by ER retention of both LIPC dimer and LPL dimer (Peterfy et al. 2007).
R-HSA-6785181 (Reactome) Hepatic triacylglycerol lipase (LIPC, and lipoprotein lipase, LPL) are dimeric lipases (Hill et al. 1997) that hydrolyse triglycerides from circulating lipoproteins thereby playing important roles in lipoprotein remodeling and uptake. LIPC dimer (as well as LPL dimer) binds to an ER membrane protein known as lipase maturation factor 1 (LMF1) which can mediate secretion and enzymatic maturation of these lipases (Doolittle et al. 2009, Babilonia-Rosa & Neher 2014). Another family member, LMF2, may function as LMF1 based on similarity. Defects in LMF1 can cause combined lipase deficiency (CLD; MIM:246650), characterised by hypertriglyceridemia caused by ER retention of both LIPC and LPL (Peterfy et al. 2007).
R-HSA-6785213 (Reactome) The hepatic triacylglycerol lipase dimer (LIPC dimer) requires binding to heparin for stability of the homodimer (Ben-Zeev et al. 2011).
R-HSA-6813720 (Reactome) NCEH1 (neutral cholesterol ester hydrolase) hydrolyzes cholesterol esters to form cholesterol (CHOL) and free fatty acids (LCFA). In both humans (Igarashi et al. 2010a) and mice (Igarashi et al. 2010b, Okazaki et al. 2008, Sakai et al. 2014 ) NCEH1 associated with the endoplasmic reticulum membrane appears to play a major role in cholesterol ester hydrolysis in macrophages. Free CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles.
R-HSA-8854408 (Reactome) Apolipoprotein B receptor (APOBR dimer) is a dimeric lipid binding receptor on the surface of macrophages. It can bind to and internalise dietary triglyceride-rich lipoproteins (TRLs) and hypertriglyceridemic very low density lipoproteins (HTG-VLDLs), both represented here by VLDL (Gianturco et al. 1998, Brown et al. 2000). APOBR dimer binds to APO-B48 in TRLs or the APO-B48 equivalent domain of APO-B100 in HTG-VLDLs (Bradley et al. 1999). Macrophages can play multifunctional roles in the pathogenesis and progression of atherosclerosis, in which they are important for intracellular lipid accumulation and foam cell formation. Lipid-filled foam cells are seen in atherosclerotic lesions (Brown et al. 2000, Takahashi et al. 2002). PPAR alpha and gamma activators and the blood cholesterol-lowering statin pitavastatin suppress the APOBR pathway in vivo, diminishing APOBR-mediated macrophage lipid accumulation and suggesting an antiatherogenic effect for these suppressors (Haraguchi et al. 2003, Kawakami et al. 2005).
R-HSA-8854462 (Reactome) Very low-density lipoproteins (VLDLs) are produced in the liver to transport endogenous triglycerides, phospholipids, cholesterol, and cholesteryl esters in the hydrophilic environment of the bloodstream. They comprise triglycerides (50-60%), cholesterol (10-12%), cholesterol esters (4-6%), phospholipids (18-20%), and apolipoprotein B (8-12%). Of the protein content, two other apolipoproteins are constituents; apolipoprotein C-I (APOC around 20%) (Westerterp et al. 2007) and apolipoprotein C4 (APOC4, minor amount) (Kotite et al. 2003). After release from the liver, circulating VLDL particles can bind very low-density lipoprotein receptors (VLDLR) (Sakai et al. 1994) on extra-hepatic target cells and undergo endocytosis (Go & Mani 2012). VLDL uptake by VLDLR represents a minor contribution towards VLDL metabolism. The majority of VLDL is catalysed by lipoprotein lipase (LPL) which hydrolyses TAGs from VLDL, converting it to intermediate-density lipoprotein (IDL). IDL can be further hydrolysed by hepatic lipase to cholesterol-rich low-density lipoprotein (LDL).

VLDLR consists of five functional domains that resemble the LDL receptor. It is highly expressed in tissues that actively metabolise fatty acids as a source of energy. Binding of VLDLs to VLDLR appears to be inhibited by apolipoprotein C-I (APOC1), therby slowing the clearance of triglyceride-rich lipoproteins from the circulation (Westerterp et al. 2007). The APOE/C1/C4/C2 gene cluster is closely associated with plasma lipid levels, atherosclerotic plaque formation, and thereby implicated in the development of coronary artery disease and Alzheimer’s disease (Xu et al. 2015).
R-HSA-8854628 (Reactome) The E3 ubiquitin-protein ligase (MYLIP, aka IDOL) mediates the ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. It acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating degradation of LDLR (Hong et al. 2010). Despite some similarities, the MYLIP and PCSK9 ubiquitination pathways for controlling (V)LDLR abundance appear to be independent of each other. MYLIP is a transcriptional target of liver X receptors (NR1H2 and NR1H3), which can increase MYLIP expression and hence decerease (V)LDLR levels (Zelcer et al. 2009, Hong et al. 2010, Sorrentino & Zelcer 2010, Zhang et al. 2012).
R-HSA-8855111 (Reactome) Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of plasma cholesterol homeostasis by binding to low-density lipid receptor family members and promoting their degradation in lysosomes (Poirier et al. 2008). In mice, it was observed that circulating PCSK9 can regulate VLDLR protein levels in adipose tissue and thereby, fat accumulation. The absence of PCSK9 led to an increase in lipid uptake resulting in adipocyte hypertrophy which was LDLR-independent (Roubtsova et al. 2011). Whether increased fat deposition also occurs in humans lacking functional PCSK9 remains to be elucidated.
R-HSA-8855130 (Reactome) Once proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to very low-density lipoprotein receptor (VLDLR), the resultant complex is internalised via the canonical clathrin-dependent endocytic machinery. This degradation route that does not require ubiquitination of the cytoplasmic tail of the receptor and does not involve proteasomal or autophagy pathways. The PCSK9:VLDLR:Clathrin-coated vesicle complex translocates from the plasma membrane, via endosomes to the lysosomal membrane where the receptor is degraded (Zhang et al. 2007, Poirier et al. 2008).
R-HSA-8855131 (Reactome) Once proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to very low-density lipoprotein receptor (VLDLR), the resultant complex is internalised via the canonical clathrin-dependent endocytic machinery. This degradation route that does not require ubiquitination of the cytoplasmic tail of the receptor and does not involve proteasomal or autophagy pahtways (Zhang et al. 2007, Poirier et al. 2008).
R-HSA-8856525 (Reactome) Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Angiopoietin-like protein 8 (ANGPTL8, aka betatrophin, lipasin) can regulate ANGPTL3 by binding to and promoting cleavage of it, thereby further activating ANGPTL3 (a protein that plays a critical role in the regulation of triglyceride and cholesterol plasma levels, via reversible inhibition of lipoprotein lipase activity) (Ren et al. 2012, Quagliarini et al. 2012, Li & Teng 2014). The exact mechanism of action of ANGPTL8 on ANGPTL3 is poorly understood.
R-HSA-8857928 (Reactome) Lipoprotein lipase (LPL) is mainly produced by adipocytes and myocytes but is also involved in hydrolysing triglyceride-rich lipoproteins in the lumen of capillaries of heart, adipose tissue, and skeletal muscle. Heparan sulfate proteoglycan (HSPG) serves as an membrane anchor for LPL dimer but for LPL to reach its site of action in capillaries, it binds to glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), an endothelial cell membrane-bound protein. Once bound, GPIHBP1 transports LPL from within interstitial spaces, across endothelial cells to the capillary lumen (Gin et al. 2007, Young et al. 2011, Adeyo et al. 2012). Defects in GPIHBP1 can cause mislocalisation of LPL leading to severe hypertriglyceridaemia and hyperlipoproteinemia type ID (MIM:615947) (Adeyo et al. 2012, Wang & Hegele 2007, Beigneux et al. 2009, Beigneux et al. 2015).
R-HSA-8858252 (Reactome) Vigilin (HDL-binding protein, HDLBP) predominantly resides on most human cell membranes and binds high-density lipoproteins (HDLs). Although its role remains unclear, Vigilin may mediate removal of excess intracellular cholesterol (Bocharov et al. 2001).
R-HSA-8865667 (Reactome) Lysosomal acid lipase/cholesteryl ester hydrolase (LIPA, aka lysosomal acid lipase, LAL) is structurally related to previously described enteric acid lipases and catalyses the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins (LDLs) (Anderson & Sando 1991, Ameis et al. 1994). LIPA is catalytically active in monomeric form. Defects in LIPA can cause Wolman disease (WOD; MIM:278000), a lysosomal lipid storage disorder where cholesteryl esters and triglycerides accumulate in most tissues of the body. WOD occurs in infancy and is nearly always fatal before the age of 1 (Anderson et al. 1994, Du et al. 1998).

Atherosclerosis is characterised by the accumulation of excess cholesterol in the artery wall. In later stages of atherosclerosis, both free cholesterol and cholesteryl ester droplets accumulate within the lysosome. As the cholesterol level increases, it inhibits the proton pumping ability of the vATPases, the pH inside the lysosome increases and renders LIPA catalytically inactive, contributing further to the progression of atherosclerosis (Dubland & Francis 2015).
R-HSA-8866304 (Reactome) The assembly of very low-density lipoprotein (VLDL) occurs in two steps (Olofsson et al. 2000). In the second step, pre-VLDL in the smooth ER lumen binds the major lipids that form bona fide VLDL; triacylglycerols (TAG) (50%), phospholipids (PL) (20%), cholesterol (CHOL) (10%) and cholesteryl esters (CHEST) (5%).
R-HSA-8866308 (Reactome) For the formation of bona fide VLDL, pre-VLDL must translocate from the rough ER membrane to smooth ER lumen where it acquires the major lipids (Olofsson et al. 2000).
R-HSA-8866321 (Reactome) Newly formed very low-density lipoprotein (VLDL) released from the liver can acquire lipoproteins in the circulation. Apolipoprotein C-I (APOC1) is a 6.6 kDa apolipoprotein that is synthesised mainly in the liver but also in other tissues. It is a constituent of triglyceride-rich lipoproteins (around 10% of the protein of VLDLs and 2% of HDLs) that slow the circulatory clearance of triglyceride-rich lipoproteins by a variety of mechanisms. As well as binding and inhibiting triglyceride-rich lipoprotein uptake by the very low-density lipoprotein receptor (VLDLR), it can also binds free fatty acids (FAs) in the circulation, reducing their uptake by cells (Shachter 2001, Hansen et al. 2011). A minor constituent of VLDL is apolipoprotein IV (APO4) (Kotite et al. 2003).
R-HSA-8866327 (Reactome) Newly formed very low-density lipoprotein (VLDL) is released from the liver to the circulation (Tiwari & Siddiqi 2012).
R-HSA-8866329 (Reactome) The assembly of very low-density lipoprotein (VLDL) occurs in two steps (Olofsson et al. 2000). In the first step, apolipoprotein B-100 (APOB(28-4563), APOB-100) is co- and post-translationally lipidated by MTP (microsomal triacylglycerol transfer protein) in the form of a MTP:PDI (protein disulfide isomerase) heterodimer (Gordon et al. 1995), forming a pre-VLDL. This occurs in the rough endoplasmic reticulum (RER) lumen. The pre-VLDL is loosely associated with the RER membrane. MTP in vitro binds small amounts of PL and TAG (annotated here as one molecule of each) and efficiently transfers the bound lipid between membranes (Atzel & Wetterau 1994). In vivo, MTP:PDI directly interacts with APOB-100 polypeptide (Wu et al. 1996), and is thought to transfer lipid from the endoplasmic reticulum membrane to nascent APOB-100. In humans, APOB-100 is expressed in the liver and forms VLDL whereas APOB-48 is expressed in the intestine and forms chylomicrons.
R-HSA-8876366 (Reactome) Once low-density lipoprotein (LDL) is freed from the LDLR to the endosomal lumen, it translocates to the lysosomal lumen for degradation via a receptor-mediated endocytotic mechanism (Goldstein et al. 1979).
R-HSA-8876472 (Reactome) In macrophages, the hydrolysis of cholesteryl esters (CHESTs) is the rate-limiting step in the removal of free cholesterol (CHOL) from these cells. CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles. Accumulation of CHESTs in macrophage foam cells is key to atherosclerotic plaque formation (Dubland & Francis 2015). Exit from lysosomes of CHOL derived from the hydrolysis of CHESTs in low-density lipoproteins (LDLs) requires the concerted effort of two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. In the first step, NPC2 binds unesterified CHOL that has been released from LDLs in the lumen of lysosomes (Liou et al. 2006).
R-HSA-8876484 (Reactome) In macrophages, the hydrolysis of cholesteryl esters (CHESTs) is the rate-limiting step in the removal of free cholesterol (CHOL) from these cells. CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles. Accumulation of CHESTs in macrophage foam cells is key to atherosclerotic plaque formation (Dubland & Francis 2015). Exit from lysosomes of CHOL derived from the hydrolysis of CHESTs in low-density lipoproteins (LDLs) requires the concerted effort of two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. In the second step, NPC2 transfers CHOL to the CHOL-binding pocket of the N-terminal domain of NPC1 (Infante et al. 2008). During the transfer of CHOL from NPC2 to NPC1, the orientation of CHOL is reversed, allowing insertion of its isooctyl side chain into the outer lysosomal membrane (Kwon et al. 2009).
R-HSA-8876485 (Reactome) In macrophages, the hydrolysis of cholesteryl esters (CHESTs) is the rate-limiting step in the removal of free cholesterol (CHOL) from these cells. CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles. Accumulation of CHESTs in macrophage foam cells is key to atherosclerotic plaque formation (Dubland & Francis 2015). CHOL is positioned on the outer membrane of lysosomes and translocates to the ER membrane where it can be re-esterified for storage. The mechanism of translocation is currently unknown (Infante et al. 2008).
R-HSA-8876696 (Reactome) Excess cellular cholesterol (CHOL) is esterified and stored as cholesteryl ester (CHEST). The conversion is catalysed by the ER membrane-residing sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT 2, aka acyl-coenzyme A:cholesterol acyltransferase 1 and 2, ACAT1 and 2) (Chang et al. 1993, Oelkers et al. 1998, Lin et al. 1999). CHESTs are usually present at low levels in most cells but chronic accumulation of CHEST in macrophages causes these cells to appear foamy and is a characteristic of early stage atherosclerosis (Becker et al. 1994). The SOAT enzymes are being investigated as potential drug targets for atherosclerosis and for Alzheimer's disease (Chang et al. 2009). Alzheimer's disease is a prevalent neurodegenerative disease, characterised by a large extracellular accumulation of amyloid plaques, composed mainly of beta-amyloid peptide aggregates. Increases in free cholesterol in the membrane, which can be caused by inhibiting ACAT1, can lead to the decrease of amyloid precursor protein processing. Pharmacological inhibitors of ACAT1 are potential treatment routes for Alzheimer's disease (Puglielli et al. 2001, Chang et al. 2009, Zhu et al. 2015).
R-HSA-8876731 (Reactome) Cholesterol that has been esterified by sterol O-acyltransferases at the ER membrane to cholesteryl esters (CHESTs) are stored in lipid particles present in the cytosol (Daugherty et al. 2008).
R-HSA-8933258 (Reactome) The human lipolysis-stimulated lipoprotein receptor (LSR, LISCH) probably plays a role in the clearance of triglyceride-rich lipoproteins from blood, allowing their subsequent uptake into cells. Its affinity is highest for those lipoproteins most susceptible to lipolysis such as chylomicrons, LDL and VLDL. Human LSR function is inferred from mouse Lsr expression, functional and gene silencing studies (Yen et al. 1999, Mesli et al. 2004, Yen et al. 2008). Lsr inactivation in mice during embryogenesis resulted in death and indicated expression of Lsr was critical for liver and embryonic development (Mesli et al. 2004). This reaction shows LSR binding LDL.
R-HSA-8933292 (Reactome) The human lipolysis-stimulated lipoprotein receptor (LSR, LISCH) probably plays a role in the clearance of triglyceride-rich lipoproteins from blood, allowing their subsequent uptake into cells. Its affinity is highest for those lipoproteins most susceptible to lipolysis such as chylomicrons, LDL and VLDL. Human LSR function is inferred from mouse Lsr expression, functional and gene silencing studies (Yen et al. 1999, Mesli et al. 2004, Yen et al. 2008). Lsr inactivation in mice during embryogenesis resulted in death and indicated expression of Lsr was critical for liver and embryonic development (Mesli et al. 2004). This reaction shows LSR binding VLDL.
R-HSA-8937442 (Reactome) In macrophage foam cells, the hydrolysis of cholesteryl esters (CHESTs) is the rate-limiting step in the removal of free cholesterol (CHOL) from these cells. CHOL is transported via transport vesicles and can be used for cellular functions or removed from the cell by ABCA1 to create new HDL particles. Accumulation of CHESTs in macrophage foam cells is key to atherosclerotic plaque formation and occurs as a result of an imbalance between CHOL influx and efflux pathways. The main hydrolase that hydrolyses CE in macrophages is neutral cholesterol ester hydrolase 1 (NCEH1). Carboxylesterases (CESs), usually involved in the hydrolysis of drugs, can also hydrolyse CHESTs with CES1 responsible for >70% of the total CES hydrolytic activity in macrophages, thus playing an important antiatherogenic role. CES1 knockdown studies reveal a compensatory increase in the expression of CES3, expressed at <30% of the level of CES1 in human macrophages, which restores intracellular CHEST hydrolytic activity and CHOL efflux (Zhao et al. 2012). Human CES3 isoproteins are predicted to be either secreted or retained in the cytosol (Holmes et al. 2010) but the exact location is currently unknown.
R-HSA-8980228 (Reactome) Dimeric lipase G (LIPG) catalyzes the hydrolysis of triglycerides (TAG) associated with high-density lipoprotein particles to diglycerides (DAG) and long-chain fatty acids (LCFA) (Griffon et al. 2009).
SAR1BArrowR-HSA-174587 (Reactome)
SCARB1-2ArrowR-HSA-349638 (Reactome)
SCARB1-2R-HSA-349637 (Reactome)
SOAT1,2mim-catalysisR-HSA-8876696 (Reactome)
TAGR-HSA-8866304 (Reactome)
TAGsArrowR-HSA-349638 (Reactome)
TAGsR-HSA-174741 (Reactome)
TAGsR-HSA-174786 (Reactome)
TAGsR-HSA-5694109 (Reactome)
TAGsR-HSA-8866329 (Reactome)
TAGsR-HSA-8980228 (Reactome)
TG-depleted chylomicronArrowR-HSA-174757 (Reactome)
TG-depleted chylomicronR-HSA-174690 (Reactome)
Ub-K839-VLDLRArrowR-HSA-8854628 (Reactome)
VLDL (-APOC1,C4)ArrowR-HSA-8866327 (Reactome)
VLDL (-APOC1,C4)R-HSA-8866321 (Reactome)
VLDL:PCSK9:Clathrin:AP2ArrowR-HSA-8855130 (Reactome)
VLDL:PCSK9:Clathrin:AP2ArrowR-HSA-8855131 (Reactome)
VLDL:PCSK9:Clathrin:AP2R-HSA-8855130 (Reactome)
VLDL:PCSK9ArrowR-HSA-8855111 (Reactome)
VLDL:PCSK9R-HSA-8855131 (Reactome)
VLDL:VLDLRArrowR-HSA-8854462 (Reactome)
VLDLArrowR-HSA-8866304 (Reactome)
VLDLArrowR-HSA-8866321 (Reactome)
VLDLR-HSA-8854408 (Reactome)
VLDLR-HSA-8854462 (Reactome)
VLDLR-HSA-8866327 (Reactome)
VLDLR-HSA-8933292 (Reactome)
VLDLRR-HSA-8854462 (Reactome)
VLDLRR-HSA-8854628 (Reactome)
VLDLRR-HSA-8855111 (Reactome)
ZDHHC8mim-catalysisR-HSA-5682084 (Reactome)
acyl-CoAR-HSA-8876696 (Reactome)
albumin:2-lysophosphatidylcholine complexArrowR-HSA-264679 (Reactome)
apoA-I:CUBN:AMN complexArrowR-HSA-264848 (Reactome)
apoA-I:CUBN:AMN complexR-HSA-264834 (Reactome)
cholesterol estersArrowR-HSA-349638 (Reactome)
chylomicron

remnant:apoE

complex
ArrowR-HSA-174624 (Reactome)
chylomicron

remnant:apoE

complex
ArrowR-HSA-174739 (Reactome)
chylomicron

remnant:apoE

complex
R-HSA-174657 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ArrowR-HSA-174657 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ArrowR-HSA-174706 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
ArrowR-HSA-174808 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
R-HSA-174624 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
R-HSA-174706 (Reactome)
chylomicron

remnant:apoE:LDLR

complex
R-HSA-174808 (Reactome)
chylomicron remnantArrowR-HSA-174690 (Reactome)
chylomicron remnantR-HSA-174739 (Reactome)
chylomicronArrowR-HSA-174660 (Reactome)
chylomicronR-HSA-174757 (Reactome)
discoidal HDL:cholesterolArrowR-HSA-266089 (Reactome)
discoidal HDLArrowR-HSA-216756 (Reactome)
discoidal HDLArrowR-HSA-264689 (Reactome)
discoidal HDLArrowR-HSA-349657 (Reactome)
discoidal HDLR-HSA-264678 (Reactome)
discoidal HDLR-HSA-266089 (Reactome)
enlarged spherical HDLArrowR-HSA-266299 (Reactome)
nascent chylomicronArrowR-HSA-174587 (Reactome)
nascent chylomicronArrowR-HSA-174741 (Reactome)
nascent chylomicronR-HSA-174587 (Reactome)
nascent chylomicronR-HSA-174660 (Reactome)
phosphatidylcholinesR-HSA-264695 (Reactome)
pre-VLDLArrowR-HSA-8866308 (Reactome)
pre-VLDLArrowR-HSA-8866329 (Reactome)
pre-VLDLR-HSA-8866304 (Reactome)
pre-VLDLR-HSA-8866308 (Reactome)
pre-beta HDLArrowR-HSA-349638 (Reactome)
pre-beta HDLR-HSA-349657 (Reactome)
spherical HDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-IIIArrowR-HSA-174690 (Reactome)
spherical HDL:apoC-II:apoC-III:apoEArrowR-HSA-266303 (Reactome)
spherical HDL:apoC-II:apoC-III:apoER-HSA-174660 (Reactome)
spherical

HDL:triacylglycerol

complex
ArrowR-HSA-266328 (Reactome)
spherical HDL:SR-BI complexArrowR-HSA-349637 (Reactome)
spherical HDL:SR-BI complexR-HSA-349638 (Reactome)
spherical HDLArrowR-HSA-174660 (Reactome)
spherical HDLArrowR-HSA-266310 (Reactome)
spherical HDLR-HSA-174690 (Reactome)
spherical HDLR-HSA-266299 (Reactome)
spherical HDLR-HSA-266303 (Reactome)
spherical HDLR-HSA-266315 (Reactome)
spherical HDLR-HSA-266328 (Reactome)
spherical HDLR-HSA-349404 (Reactome)
spherical HDLR-HSA-349637 (Reactome)
spherical HDLR-HSA-8858252 (Reactome)
torcetrapibR-HSA-349404 (Reactome)

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