Triglyceride metabolism (Homo sapiens)

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3, 4, 20251, 2, 481210, 17, 18, 287, 199, 1322262416, 2414, 23, 2715, 21, 24lipid dropletmitochondrial matrixcytosolendoplasmic reticulum lumenLCFA(-) ADPCHESTFABP4 GlycerolLCFA(-)ABHD5 H2OFABP5 atR-PALM1-acyl LPALIPEperilipin:CGI-58complexBH4PRKACG PiFABP4 LPIN1,2,3DHAPphosphorylated HSLdimer:FABP4 complex1,2-daG3PH2OFABP12 FABP7 PLIN3FABP3 p-S649,S650-LIPE GK,GK2,GK3PATP2-acylglycerolH2OABHD5DGAT1 PiDGAT1 tetramerFABP12 TAGPPP1CB AGMOGPAT2 FABPs:LCFAADPFABP4 TAGLPIN1 ATPPALM(-)PLIN1DGAT2acyl-CoAPNPLA4MOGAT1 MOGAT3 FABPsMOGAT1,2,3FABP6 LPIN2 FADH2FABP2 PPP1CC H2OFABP1 Piphosphorylated HSLdimerPP1 catalyticsubunitFABP9 p-S649,S650-LIPE FACoAGPAM or GPAT2DAGGK3P phosphorylated HSLdimerGPAM(1-828) GK2 FABP3 FABP6 LPIN3 CAV1Glycerolfatty aldehydeMOGAT2 PRKACA 2AGDAGFADO2PPP1CA H2OGPD2MGLLPRKACB CoA-SHFABP4FACoAp-S649,S650-LIPEFABP1 H2OG3PFABP2 G3PCoA-SHPKA catalyticsubunitp-S81,S277-PLIN1FABP7 atROLalkylglycerolFABP9 FABP5 TAGGK CHOLPNPLA5DAGBH2p-S649,S650-LIPE H2OPLIN1 5, 624112425115, 6


Fatty acids derived from the diet and synthesized de novo in the liver are assembled into triglycerides (triacylglycerols) for transport and storage. Synthesis proceeds in steps of conversion of fatty acyl-CoA to phosphatidic acid, conversion of phosphatidic acid to diacylglycerol, and conversion of diacylglycerol to triacylglycerol (Takeuchi & Reue 2009).
Hydrolysis of triacylglycerol to yield fatty acids and glycerol is a tightly regulated part of energy metabolism. A central part in this regulation is played by hormone-sensitive lipase (HSL), a neutral lipase abundant in adipocytes and skeletal and cardiac muscle, but also abundant in ovarian and adrenal tissue, where it mediates cholesterol ester hydrolysis, yielding cholesterol for steroid biosynthesis. The hormones to which it is sensitive include catecholamines (e.g., epinephrine), ACTH, and glucagon, all of which trigger signaling cascades that lead to its phosphorylation and activation, and insulin, which sets off events leading to its dephosphorylation and inactivation (Kraemer & Shen 2002).

The processes of triacylglycerol and cholesterol ester hydrolysis are also regulated by subcellular compartmentalization: these lipids are packaged in cytosolic particles and the enzymes responsible for their hydrolysis, and perhaps for additional steps in their metabolism, are organized at the surfaces of these particles (e.g., Brasaemle et al. 2004). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 8979227
Reactome version: 66
Reactome Author 
Reactome Author: Jassal, Bijay, Gillespie, Marc E, Gopinathrao, G, D'Eustachio, Peter

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  1. Shindou H, Shimizu T.; ''Acyl-CoA:lysophospholipid acyltransferases.''; PubMed Europe PMC Scholia
  2. Chen YQ, Kuo MS, Li S, Bui HH, Peake DA, Sanders PE, Thibodeaux SJ, Chu S, Qian YW, Zhao Y, Bredt DS, Moller DE, Konrad RJ, Beigneux AP, Young SG, Cao G.; ''AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase.''; PubMed Europe PMC Scholia
  3. Kraemer FB, Shen WJ.; ''Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis.''; PubMed Europe PMC Scholia
  4. Takeuchi K, Reue K.; ''Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis.''; PubMed Europe PMC Scholia
  5. Hostetler HA, McIntosh AL, Atshaves BP, Storey SM, Payne HR, Kier AB, Schroeder F.; ''L-FABP directly interacts with PPARalpha in cultured primary hepatocytes.''; PubMed Europe PMC Scholia
  6. Wolfrum C, Borrmann CM, Borchers T, Spener F.; ''Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.''; PubMed Europe PMC Scholia
  7. Wakimoto K, Chiba H, Michibata H, Seishima M, Kawasaki S, Okubo K, Mitsui H, Torii H, Imai Y.; ''A novel diacylglycerol acyltransferase (DGAT2) is decreased in human psoriatic skin and increased in diabetic mice.''; PubMed Europe PMC Scholia
  8. Smith AJ, Sanders MA, Thompson BR, Londos C, Kraemer FB, Bernlohr DA.; ''Physical association between the adipocyte fatty acid-binding protein and hormone-sensitive lipase: a fluorescence resonance energy transfer analysis.''; PubMed Europe PMC Scholia
  9. Grimsey N, Han GS, O'Hara L, Rochford JJ, Carman GM, Siniossoglou S.; ''Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2.''; PubMed Europe PMC Scholia
  10. Yu JH, Lee YJ, Kim HJ, Choi H, Choi Y, Seok JW, Kim JW.; ''Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation.''; PubMed Europe PMC Scholia
  11. Hughes ML, Liu B, Halls ML, Wagstaff KM, Patil R, Velkov T, Jans DA, Bunnett NW, Scanlon MJ, Porter CJ.; ''Fatty Acid-binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-activated Receptor α in a Ligand-selective Manner.''; PubMed Europe PMC Scholia
  12. Smathers RL, Petersen DR.; ''The human fatty acid-binding protein family: evolutionary divergences and functions.''; PubMed Europe PMC Scholia
  13. Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K.; ''Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.''; PubMed Europe PMC Scholia
  14. Fernandez-Alvarez J, Conget I, Rasschaert J, Sener A, Gomis R, Malaisse WJ.; ''Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients.''; PubMed Europe PMC Scholia
  15. Gao JG, Shih A, Gruber R, Schmuth M, Simon M.; ''GS2 as a retinol transacylase and as a catalytic dyad independent regulator of retinylester accretion.''; PubMed Europe PMC Scholia
  16. Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW.; ''Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.''; PubMed Europe PMC Scholia
  17. Lockwood JF, Cao J, Burn P, Shi Y.; ''Human intestinal monoacylglycerol acyltransferase: differential features in tissue expression and activity.''; PubMed Europe PMC Scholia
  18. Cheng D, Nelson TC, Chen J, Walker SG, Wardwell-Swanson J, Meegalla R, Taub R, Billheimer JT, Ramaker M, Feder JN.; ''Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption.''; PubMed Europe PMC Scholia
  19. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV.; ''Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members.''; PubMed Europe PMC Scholia
  20. Brasaemle DL, Dolios G, Shapiro L, Wang R.; ''Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes.''; PubMed Europe PMC Scholia
  21. Gao JG, Simon M.; ''Molecular screening for GS2 lipase regulators: inhibition of keratinocyte retinylester hydrolysis by TIP47.''; PubMed Europe PMC Scholia
  22. Watschinger K, Keller MA, Golderer G, Hermann M, Maglione M, Sarg B, Lindner HH, Hermetter A, Werner-Felmayer G, Konrat R, Hulo N, Werner ER.; ''Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes.''; PubMed Europe PMC Scholia
  23. Lehn DA, Brown LJ, Simonson GD, Moran SM, MacDonald MJ.; ''The sequence of a human mitochondrial glycerol-3-phosphate dehydrogenase-encoding cDNA.''; PubMed Europe PMC Scholia
  24. Gao JG, Simon M.; ''A comparative study of human GS2, its paralogues, and its rat orthologue.''; PubMed Europe PMC Scholia
  25. Cheng D, Meegalla RL, He B, Cromley DA, Billheimer JT, Young PR.; ''Human acyl-CoA:diacylglycerol acyltransferase is a tetrameric protein.''; PubMed Europe PMC Scholia
  26. Ohira RH, Dipple KM, Zhang YH, McCabe ER.; ''Human and murine glycerol kinase: influence of exon 18 alternative splicing on function.''; PubMed Europe PMC Scholia
  27. Matsutani A, Takeuchi Y, Ishihara H, Kuwano S, Oka Y.; ''Molecular cloning of human mitochondrial glycerophosphate dehydrogenase gene: genomic structure, chromosomal localization, and existence of a pseudogene.''; PubMed Europe PMC Scholia
  28. Winter A, van Eckeveld M, Bininda-Emonds OR, Habermann FA, Fries R.; ''Genomic organization of the DGAT2/MOGAT gene family in cattle (Bos taurus) and other mammals.''; PubMed Europe PMC Scholia


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101625view11:49, 1 November 2018ReactomeTeamreactome version 66
101161view21:35, 31 October 2018ReactomeTeamreactome version 65
100687view20:08, 31 October 2018ReactomeTeamreactome version 64
100237view16:53, 31 October 2018ReactomeTeamreactome version 63
99789view15:18, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99340view12:47, 31 October 2018ReactomeTeamreactome version 62
93673view11:30, 9 August 2017ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
1,2-daG3PMetaboliteCHEBI:29089 (ChEBI)
1-acyl LPAMetaboliteCHEBI:16975 (ChEBI)
2-acylglycerolMetaboliteCHEBI:17389 (ChEBI)
2AGMetaboliteCHEBI:17389 (ChEBI)
ABHD5 ProteinQ8WTS1 (Uniprot-TrEMBL)
ABHD5ProteinQ8WTS1 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGMOProteinQ6ZNB7 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BH2MetaboliteCHEBI:15375 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CAV1ProteinQ03135 (Uniprot-TrEMBL)
CHESTMetaboliteCHEBI:17002 (ChEBI)
CHOLMetaboliteCHEBI:16113 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI)
DGAT1 ProteinO75907 (Uniprot-TrEMBL)
DGAT1 tetramerComplexR-HSA-200109 (Reactome)
DGAT2ProteinQ96PD7 (Uniprot-TrEMBL)
DHAPMetaboliteCHEBI:16108 (ChEBI)
FABP1 ProteinP07148 (Uniprot-TrEMBL) As inferred from mouse, FABP1 localizes to the nucleus where it may deliver lipids to PPARA.
FABP12 ProteinA6NFH5 (Uniprot-TrEMBL)
FABP2 ProteinP12104 (Uniprot-TrEMBL)
FABP3 ProteinP05413 (Uniprot-TrEMBL)
FABP4 ProteinP15090 (Uniprot-TrEMBL)
FABP4ProteinP15090 (Uniprot-TrEMBL)
FABP5 ProteinQ01469 (Uniprot-TrEMBL)
FABP6 ProteinP51161 (Uniprot-TrEMBL)
FABP7 ProteinO15540 (Uniprot-TrEMBL)
FABP9 ProteinQ0Z7S8 (Uniprot-TrEMBL)
FABPs:LCFAComplexR-HSA-5334829 (Reactome)
FABPsComplexR-HSA-5334833 (Reactome)
FACoAMetaboliteCHEBI:37554 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI)
FADH2MetaboliteCHEBI:17877 (ChEBI)
G3PMetaboliteCHEBI:15978 (ChEBI)
GK ProteinP32189 (Uniprot-TrEMBL)
GK,GK2,GK3PComplexR-HSA-3769055 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
GK2 ProteinQ14410 (Uniprot-TrEMBL)
GK3P ProteinQ14409 (Uniprot-TrEMBL)
GPAM or GPAT2ComplexR-HSA-549113 (Reactome)
GPAM(1-828) ProteinQ9HCL2 (Uniprot-TrEMBL)
GPAT2 ProteinQ6NUI2 (Uniprot-TrEMBL)
GPD2ProteinP43304 (Uniprot-TrEMBL)
GlycerolMetaboliteCHEBI:17754 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
LCFA(-) MetaboliteCHEBI:57560 (ChEBI)
LCFA(-)MetaboliteCHEBI:57560 (ChEBI)
LIPEProteinQ05469 (Uniprot-TrEMBL)
LPIN1 ProteinQ14693 (Uniprot-TrEMBL)
LPIN1,2,3ComplexR-HSA-549151 (Reactome)
LPIN2 ProteinQ92539 (Uniprot-TrEMBL)
LPIN3 ProteinQ9BQK8 (Uniprot-TrEMBL)
MGLLProteinQ99685 (Uniprot-TrEMBL)
MOGAT1 ProteinQ96PD6 (Uniprot-TrEMBL)
MOGAT1,2,3ComplexR-HSA-6800338 (Reactome)
MOGAT2 ProteinQ3SYC2 (Uniprot-TrEMBL)
MOGAT3 ProteinQ86VF5 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PALM(-)MetaboliteCHEBI:7896 (ChEBI)
PKA catalytic subunitComplexR-HSA-111920 (Reactome)
PLIN1 ProteinO60240 (Uniprot-TrEMBL)
PLIN1ProteinO60240 (Uniprot-TrEMBL)
PLIN3ProteinO60664 (Uniprot-TrEMBL)
PNPLA4ProteinP41247 (Uniprot-TrEMBL)
PNPLA5ProteinQ7Z6Z6 (Uniprot-TrEMBL)
PP1 catalytic subunitComplexR-HSA-163538 (Reactome)
PPP1CA ProteinP62136 (Uniprot-TrEMBL)
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1CC ProteinP36873 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
TAGMetaboliteCHEBI:17855 (ChEBI)
acyl-CoAMetaboliteCHEBI:17984 (ChEBI)
alkylglycerolMetaboliteCHEBI:52575 (ChEBI)
atR-PALMMetaboliteCHEBI:17616 (ChEBI)
atROLMetaboliteCHEBI:17336 (ChEBI)
fatty aldehydeMetaboliteCHEBI:35746 (ChEBI)
p-S649,S650-LIPE ProteinQ05469 (Uniprot-TrEMBL)
p-S649,S650-LIPEProteinQ05469 (Uniprot-TrEMBL)
p-S81,S277-PLIN1ProteinO60240 (Uniprot-TrEMBL)
perilipin:CGI-58 complexComplexR-HSA-163495 (Reactome)
phosphorylated HSL dimer:FABP4 complexComplexR-HSA-163535 (Reactome)
phosphorylated HSL dimerComplexR-HSA-163435 (Reactome)
phosphorylated HSL dimerComplexR-HSA-163513 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
1,2-daG3PR-HSA-75899 (Reactome)
1-acyl LPAArrowR-HSA-75886 (Reactome)
2-acylglycerolArrowR-HSA-163402 (Reactome)
2-acylglycerolR-HSA-163595 (Reactome)
2AGR-HSA-6800334 (Reactome)
ABHD5ArrowR-HSA-163539 (Reactome)
ADPArrowR-HSA-163416 (Reactome)
ADPArrowR-HSA-163418 (Reactome)
ADPArrowR-HSA-75887 (Reactome)
AGMOmim-catalysisR-HSA-5696119 (Reactome)
ATPR-HSA-163416 (Reactome)
ATPR-HSA-163418 (Reactome)
ATPR-HSA-75887 (Reactome)
BH2ArrowR-HSA-5696119 (Reactome)
BH4R-HSA-5696119 (Reactome)
CAV1ArrowR-HSA-163418 (Reactome)
CHESTR-HSA-163432 (Reactome)
CHOLArrowR-HSA-163432 (Reactome)
CoA-SHArrowR-HSA-549192 (Reactome)
CoA-SHArrowR-HSA-6800334 (Reactome)
CoA-SHArrowR-HSA-75886 (Reactome)
CoA-SHArrowR-HSA-75900 (Reactome)
DAGArrowR-HSA-163551 (Reactome)
DAGArrowR-HSA-6800334 (Reactome)
DAGArrowR-HSA-75899 (Reactome)
DAGArrowR-HSA-8848338 (Reactome)
DAGArrowR-HSA-8848339 (Reactome)
DAGR-HSA-163402 (Reactome)
DAGR-HSA-549192 (Reactome)
DAGR-HSA-75900 (Reactome)
DGAT1 tetramermim-catalysisR-HSA-75900 (Reactome)
DGAT2mim-catalysisR-HSA-549192 (Reactome)
DHAPArrowR-HSA-188467 (Reactome)
FABP4R-HSA-163549 (Reactome)
FABPs:LCFAArrowR-HSA-5334794 (Reactome)
FABPsR-HSA-5334794 (Reactome)
FACoAR-HSA-549192 (Reactome)
FACoAR-HSA-75886 (Reactome)
FACoAR-HSA-75900 (Reactome)
FADH2ArrowR-HSA-188467 (Reactome)
FADR-HSA-188467 (Reactome)
G3PArrowR-HSA-75887 (Reactome)
G3PR-HSA-188467 (Reactome)
G3PR-HSA-75886 (Reactome)
GK,GK2,GK3Pmim-catalysisR-HSA-75887 (Reactome)
GPAM or GPAT2mim-catalysisR-HSA-75886 (Reactome)
GPD2mim-catalysisR-HSA-188467 (Reactome)
GlycerolArrowR-HSA-163595 (Reactome)
GlycerolArrowR-HSA-5696119 (Reactome)
GlycerolR-HSA-75887 (Reactome)
H2OArrowR-HSA-5696119 (Reactome)
H2OR-HSA-163402 (Reactome)
H2OR-HSA-163432 (Reactome)
H2OR-HSA-163489 (Reactome)
H2OR-HSA-163551 (Reactome)
H2OR-HSA-163568 (Reactome)
H2OR-HSA-163595 (Reactome)
H2OR-HSA-75899 (Reactome)
H2OR-HSA-8848338 (Reactome)
H2OR-HSA-8848339 (Reactome)
H2OR-HSA-8848355 (Reactome)
LCFA(-)ArrowR-HSA-163402 (Reactome)
LCFA(-)ArrowR-HSA-163432 (Reactome)
LCFA(-)ArrowR-HSA-163551 (Reactome)
LCFA(-)ArrowR-HSA-163595 (Reactome)
LCFA(-)ArrowR-HSA-8848338 (Reactome)
LCFA(-)ArrowR-HSA-8848339 (Reactome)
LCFA(-)R-HSA-5334794 (Reactome)
LIPEArrowR-HSA-163489 (Reactome)
LIPER-HSA-163416 (Reactome)
LPIN1,2,3mim-catalysisR-HSA-75899 (Reactome)
MGLLmim-catalysisR-HSA-163595 (Reactome)
MOGAT1,2,3mim-catalysisR-HSA-6800334 (Reactome)
O2R-HSA-5696119 (Reactome)
PALM(-)ArrowR-HSA-8848355 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-163416 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-163418 (Reactome)
PLIN1ArrowR-HSA-163539 (Reactome)
PLIN1ArrowR-HSA-163568 (Reactome)
PLIN1R-HSA-163418 (Reactome)
PLIN3TBarR-HSA-8848355 (Reactome)
PNPLA4mim-catalysisR-HSA-8848338 (Reactome)
PNPLA4mim-catalysisR-HSA-8848355 (Reactome)
PNPLA5mim-catalysisR-HSA-8848339 (Reactome)
PP1 catalytic subunitmim-catalysisR-HSA-163568 (Reactome)
PiArrowR-HSA-163489 (Reactome)
PiArrowR-HSA-163568 (Reactome)
PiArrowR-HSA-75899 (Reactome)
R-HSA-163402 (Reactome) Rat HSL catalyzes the hydrolysis of diacylglycerol to yield 2-acylglycerol + fatty acid (Fredrikson and Belfrage 1983). The human event has not been studied in detail and is inferred from the rat one.
R-HSA-163416 (Reactome) Cytosolic rat HSL is phosphorylated on serine residues 659 and 660 by protein kinase A catalytic subunit (Anthonsen et al. 1998; Su et al. 2003). Three isoforms of protein kinase A are known, but with no known differences in substrate specificity or tissue specific expression patterns, so a generic PKA (with all three forms as instances) is annotated as the catalyst of this reaction. Other serine residues in HSL can be phosphorylated both in vitro and in vivo, and while these other phosphorylations appear not to affect triacylglycerol hydrolysis by HSL directly, they may affect the efficiency with which serines 659 and 660 themselves are phosphorylated, or affect the efficiency with which HSL is translocated to cytosolic lipid particles (Holm et al. 2000).

Phosphorylation of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one. By BLAST alignment, human HSL residues 649 and 650 correspond to rat serines 659 and 660.

R-HSA-163418 (Reactome) Rat perilipin, the major protein at the surfaces of cytosolic lipid particles in adipocytes and steroidogenic cells (Blanchette-Mackie et al. 1995), is phosphorylated by protein kinase A catalytic subunit (Greenberg et al. 1991) on serine residues 81, 223, and 277 (Tansey et al. 2003). All three serine residues and the adjoining sequences that mediate phosphorylation (Cohen 1988) are conserved in mouse perilipin, while only the first and third are conserved in human perilipin. By inference, PKA targets these three mouse and two human serines as well. Phosphorylated perilipin is redistributed on the droplet surfaces (Souza et al. 1998). While two isoforms of rat perilipin protein are found on lipid particles in adipocytes, only the larger isoform appears to regulate lipolysis (Tansey et al 2003). The single human and mouse isoforms of perilipin correspond to the large rat isoform. In mouse 3T3-L1 cells, perilipin phosphorylation requires the presence of caveolin-1 at the surface of the lipid particle (Cohen et al. 2004). This positive regulatory effect of caveolin-1 is inferred for rat and human.
R-HSA-163432 (Reactome) Activated rat HSL hydrolyzes cholesterol ester to yield cholesterol + fatty acid (Fredrikson et al. 1981). The human reaction has not been studied in detail, and is inferred from the well-characterized rat one.
R-HSA-163489 (Reactome) Rat HSL is inactivated by dephosphorylation. The catalyst of this reaction is unknown. Protein phosphatases 1 and 2A are both abundant in rat adipocytes and both are active on HSL (Olsson and Belfrage 1987; Wood et al. 1993). Whether these enzymes act on phosphate groups attached to serine residues 659 and 660 of HSL is unknown, however (Holm et al. 2000). Although the reaction is annotated as though the phosphatase acts on phosphorylated HSL monomers, this also is unknown: does the HSL:FABP complex dissociate before HSL dephosphorylation (as implied here), or does dephosphorylation of HSL drive dissociation of the complex?

Dephosphorylation of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one.

R-HSA-163539 (Reactome) In unstimulated mouse 3T3-L1 adipocytes, perilipin is localized to the surfaces of cytosolic lipid particles as a complex with CGI-58. Catecholamine stimulation (and by inference glucagon stimulation) is associated with rapid dissociation of the complex and relocalization of the CGI-58 protein away from the lipid particle. The stoichiometry of the complex is unknown. Dissociation of the perilipin:CGI-58 complex appears to precede perilipin phosphorylation, although the molecular link between these two steps is unknown (Subramanian et al. 2004).

The interaction of human CGI-58 and perilipin on the lipid particle surface has not been studied in detail, so the human reaction is inferred from the well-studied mouse one. The observation that humans homozygous for CGI-58 mutations suffer from Chanarin-Dorfman Syndrome, characterized by the abnormal accumulation of triacylglycerol droplets in most tissues (Lefevre et al. 2001), provides indirect evidence that human and mouse CGI-58 proteins have similar functions.

R-HSA-163549 (Reactome) Rat FABPA associates with HSL and increases the rate of triacylglycerol hydrolysis, possibly by sequestering the released fatty acids (Shen et al. 1999; Shen et al. 2001). A similar association of HSL and FABP4 at the lipid droplet surface has been demonstrated in human adipocytes (Smith et al. 2004). The stoichiometry of the fatty acid:FABP complex is unknown. This model implies that HSL-associated FABP loaded with fatty acid should exchange with unloaded, unassociated FABP, allowing HSL to continue to work efficiently while moving newly generated fatty acids away from the lipid particle. To date, there is no evidence for or against such a shuttling process.
R-HSA-163551 (Reactome) Activated rat HSL at the lipid particle hydrolyzes triacylglycerol to yield diacylglycerol + fatty acid. In vitro, activated partially purified HSL catalyzes this reaction at only about two times the rate measured with non-activated enzyme (Fredrikson et al. 1981). The much greater rate increase caused by HSL phosphorylation in vivo appears to be due to its phosphorylation-dependent translocation to the surface of the lipid particle (Birnbaum 2003).

HSL-mediated triacylglycerol hydrolysis in humans has not been studied in detail, so the human reaction is inferred from the well-studied rat one.

R-HSA-163554 (Reactome) In primary adipocytes from young rats and in adipocytes derived from 3T3-L1 cells in vitro, phosphorylated hormone-sensitive lipase translocates from the cytosol to the surfaces of lipid particles following the phosphorylation of perilipin (Clifford et al. 2000; Su et al. 2003; Sztalryd et al. 2003)

The human reaction is inferred from the well-studied rat one.

R-HSA-163568 (Reactome) Rat perilipin is dephosphorylated by protein phosphatase 1 (Clifford et al. 1998). All three protein phosphatase 1 isoforms appear competent to carry out this reaction and there are no data to indicate which one preferentially acts on perilipin in vivo. Dephosphorylation of human perilipin has not been studied in detail, so the human reaction is inferred from the well-studied rat one.
R-HSA-163595 (Reactome) Rat monoacylglycerol lipase (MGLL) catalyzes the hydrolysis of 2-acylglycerol to yield glycerol + fatty acid (Tornqvist and Belfrage 1976; Fredrikson et al. 1986). Localization of the enzyme to lipid particles is plausible, given its low solubility and its involvement in acylglycerol metabolism, but this localization has not been directly experimentally verified. The human reaction is inferred from the well-studied rat one.
R-HSA-163602 (Reactome) While both monomeric and homodimeric forms of rat HSL protein have been detected, the predominant species, and the one with substantially greater catalytic activity when activated by phosphorylation, is the homodimer so HSL-mediated lipolysis is annotated in Reactome with dimeric phosphorylated enzyme as the catalyst. Phosphorylation appears to be required for dimerization to proceed (Shen et al. 2000).

Dimerization of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one.

R-HSA-188467 (Reactome) FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2, alias: mGPDH) and its NAD-linked cytosolic isoform (GPD1, alias:cGPDH) constitute glycerol phosphate shuttle. GPD2 catalyzes the unidirectional conversion of glycerol-3-phosphate (G-3-P) to dihydroxyacetone phosphate (DHAP) with concomitant reduction of the enzyme-bound FAD. Impaired activity of GPD2 has been suggested to be one of the primary causes of insulin secretory defects in beta-cells and thus it is a candidate gene for type 2 diabetes.
R-HSA-5334794 (Reactome) Hydrophobic compounds such as long-chain fatty acids (LCFAs) and their acyl-CoA derivatives (LCFA-CoAs) are involved in important functions within a cell such as membrane substrates, energy sources and signalling molecules. The hydrophobic nature of these compounds makes translocation between different compartments of a cell extremely difficult. Fatty acid-binding proteins (FABPs) are able to bind these hydrophobic compounds with high affinity and transport them through the cytosol for delivery to different organelles within the cell. To date, 9 human FABP-coding genes have been identified (Smathers & Petersen 2011).
R-HSA-549192 (Reactome) Diacylglycerol O-acyltransferase 1 (DGAT2) associated with the endoplasmic reticulum membrane catalyzes the reaction of 1,2-diacyl-glycerol and acyl-CoA to form triacylglycerol + CoASH (Cases et al. 2001, Wakimoto et al. 2003).
R-HSA-5696119 (Reactome) Ether lipids (alkylglycerols, glyceryl ethers) are essential components of brain membranes, protect the eye from cataract, mediate signalling processes and are required for spermatogenesis. Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin-dependent protein and is the only enzyme known to cleave the ether bond of alkylglycerols and lyso-alkylglycerol phospholipids into fatty aldehydes and glycerol derivatives (Watschinger et al. 2010).
R-HSA-6800334 (Reactome) Triacylglycerol (TG) is a non-polar acyl triester of glycerol and fatty acids. TG serves primarily as a reservoir of fatty acids for energy production. TG synthesis in all organisms occurs via the conserved canonical pathway known as the Kennedy or sn-glycerol-3-phosphate (G3P) pathway. Diacylglycerol (DAG), an intermediate in the Kennedy pathway, can also enter this pathway via an alternative route known as the remodeling pathway which dominates in the small intestine where most dietary fat is absorbed. In this pathway, monoacylglycerol is acylated, mediated by monoacylglycerol acyltransferases 1, 2 and 3 (MOGAT1, 2 and 3) to form DAG (Winter et al. 2003, Lockwood et al. 2003, Cheng et al. 2003, Yu et al. 2015).
R-HSA-75886 (Reactome) Either of GPAM or GPAT2 (glycerol-3-phosphate acyltransferase, mitochondrial; glycerol-3-phosphate acyltransferase 2, mitochondrial) associated with the outer mitochondrial membrane catalyzes the reaction of cytosolic glycerol 3-phosphate and acyl-CoA to form 1-acylglycerol 3-phosphate and CoASH. The biochemical properties and location of human GPAM have been established through studies of the recombinant protein (Chen et al. 2008); those features of GPAT2 have been inferred from the properties of its rat homologue and those of GPAM. GPAM and GPAT2 differ in their their preferences for acyl-CoA substrates (Shindou & Shimizu 2009) and in their expression patterns in the body (Takeuchi & Reue 2009).
R-HSA-75887 (Reactome) Glycerol can be a source for glycerol-3-phosphate, in which case, a phosphate form ATP is transferred to glycerol by glycerol kinase forming glycerol-3-phosphate and ADP.

R-HSA-75899 (Reactome) Lipin proteins LPIN1, 2, and 3, associated with the endoplasmic reticulum membrane, can each catalyze the hydrolysis of phosphatidate to yield 1,2-diacyl-glycerol and orthophosphate. The activities of LPIN1 and LPIN2 have been established experimentally (Grimsey et al. 2008); that of LPIN3 is inferred from its structural similarities both to its human paralogues and to its mouse ortholog (Donkor et al. 2007). Only LPIN1 has been shown to be stably associated with the endoplasmic reticulum, but all three enzymes appear to be catalytically active at that location (Grimsey et al. 2008; Donkor et al. 2007).
R-HSA-75900 (Reactome) Tetrameric diacylglycerol O-acyltransferase 1 (DGAT1) associated with the endoplasmic reticulum membrane catalyzes the reaction of 1,2-diacyl-glycerol and acyl-CoA to form triacylglycerol + CoASH (Cheng et al. 2001).
R-HSA-8848338 (Reactome) PNPLA4 (patatin-like phospholipase domain-containing protein 4, also known as GS2 and iPLA2(eta)) catalyzes the hydrolysis of TAG (triacylglycerol) to DAG (diacylglycerol) and one molecule of LCFA (long chain fatty acid). The enzyme also has transacylase activity not annotated here (Gao and Simon 2007; Jenkins et al. 2004).
R-HSA-8848339 (Reactome) PNPLA5 (patatin-like phospholipase domain-containing protein 5, also known as GS2 like) catalyzes the hydrolysis of TAG (triacylglycerol) to DAG (diacylglycerol) and one molecule of LCFA (long chain fatty acid) (Gao and Simon 2007).
R-HSA-8848355 (Reactome) PNPLA4 (patatin-like phospholipase domain-containing protein 4, also known as GS2 and iPLA2(eta)) catalyzes the hydrolysis of atR-PALM (all-trans retinyl palmitate) to atROL (all-trans retinol) and a molecule of PALM (palmitate) (Gao and Simon 2006; Gao and Simon 2007). The reaction is inhibited by cytosolic PLIN3 (perilipin 3). The enzyme may also catalyze transacylation reactions to form retinyl esters or promote the activity of other enzymes that do so (Gao et al. 2009).
TAGArrowR-HSA-549192 (Reactome)
TAGArrowR-HSA-75900 (Reactome)
TAGR-HSA-163551 (Reactome)
TAGR-HSA-8848338 (Reactome)
TAGR-HSA-8848339 (Reactome)
acyl-CoAR-HSA-6800334 (Reactome)
alkylglycerolR-HSA-5696119 (Reactome)
atR-PALMR-HSA-8848355 (Reactome)
atROLArrowR-HSA-8848355 (Reactome)
fatty aldehydeArrowR-HSA-5696119 (Reactome)
p-S649,S650-LIPEArrowR-HSA-163416 (Reactome)
p-S649,S650-LIPER-HSA-163489 (Reactome)
p-S649,S650-LIPER-HSA-163602 (Reactome)
p-S81,S277-PLIN1ArrowR-HSA-163418 (Reactome)
p-S81,S277-PLIN1R-HSA-163568 (Reactome)
perilipin:CGI-58 complexR-HSA-163539 (Reactome)
phosphorylated HSL dimer:FABP4 complexArrowR-HSA-163549 (Reactome)
phosphorylated HSL dimer:FABP4 complexmim-catalysisR-HSA-163402 (Reactome)
phosphorylated HSL dimer:FABP4 complexmim-catalysisR-HSA-163432 (Reactome)
phosphorylated HSL dimer:FABP4 complexmim-catalysisR-HSA-163551 (Reactome)
phosphorylated HSL dimerArrowR-HSA-163554 (Reactome)
phosphorylated HSL dimerArrowR-HSA-163602 (Reactome)
phosphorylated HSL dimerR-HSA-163549 (Reactome)
phosphorylated HSL dimerR-HSA-163554 (Reactome)

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