PNPLA2 encodes adipose triglyceride lipase (ATGL; also desnutrin, iPLA2-zeta, PEDF-R), a patatin-domain serine hydrolase that catalyzes the first, rate-limiting step of intracellular triacylglycerol hydrolysis, converting triacylglycerol to diacylglycerol and a fatty acid. ATGL acts on the surface of cytoplasmic lipid droplets in adipocytes and many non-adipose cells, including skeletal and cardiac muscle, and its activity is strongly stimulated by the co-activator ABHD5/CGI-58 and limited by inhibitory partners and ubiquitin-dependent degradation. Purified ATGL also shows acylglycerol transacylase activity, which generates fatty acid esters of hydroxy fatty acids, and minor phospholipase A2 and retinyl ester hydrolase activities. Biallelic loss-of-function variants cause neutral lipid storage disease with myopathy, with triacylglycerol accumulation in muscle, heart and leukocytes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004465 lipoprotein lipase activity | TAS Reactome:R-HSA-1482811 | REMOVE | Summary: Reactome-derived "lipoprotein lipase activity" for the reaction in which PNPLA2/3 hydrolyze diacylglycerol at the ER membrane. Lipoprotein lipase activity is defined for hydrolysis of triacylglycerol carried in lipoproteins; ATGL is an intracellular lipid-droplet lipase and does not act on circulating lipoproteins. Reason: The term is a mis-mapping of an intracellular acylglycerol hydrolysis reaction onto the extracellular lipoprotein lipase activity term. ATGL activity on diacylglycerol is minor compared with its triacylglycerol preference, so no replacement term is proposed; the core activity is captured by GO:0004806. Supporting Evidence: Reactome:R-HSA-1482811 patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG) PMID:15550674 It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. |
| GO:0004623 A2-type glycerophospholipase activity | IDA PMID:15364929 Identification, cloning, expression, and purification of thr... | KEEP AS NON CORE | Summary: Phospholipase A2 activity reported for recombinant iPLA2-zeta/PEDF-R in vitro, stimulated by PEDF binding in the retinal PEDF-receptor model. The activity is real in the assays described but is minor relative to triacylglycerol hydrolysis and has not been connected to the lipid-droplet lipolysis function or to the NLSDM phenotype. Reason: Experimentally supported in vitro side activity; retained but not part of the core triacylglycerol-lipase function. Supporting Evidence: PMID:15364929 we demonstrate that each possesses abundant TAG lipase activity PMID:17032652 PEDF binding stimulates the enzymatic phospholipase A(2) activity of PEDF-R. |
| GO:0004623 A2-type glycerophospholipase activity | IDA PMID:17032652 Identification of a lipase-linked cell membrane receptor for... | KEEP AS NON CORE | Summary: Phospholipase A2 activity reported for recombinant iPLA2-zeta/PEDF-R in vitro, stimulated by PEDF binding in the retinal PEDF-receptor model. The activity is real in the assays described but is minor relative to triacylglycerol hydrolysis and has not been connected to the lipid-droplet lipolysis function or to the NLSDM phenotype. Reason: Experimentally supported in vitro side activity; retained but not part of the core triacylglycerol-lipase function. Supporting Evidence: PMID:17032652 PEDF binding stimulates the enzymatic phospholipase A(2) activity of PEDF-R. PMID:17032652 has a potent phospholipase A(2) activity that liberates fatty acids, and is associated with eukaryotic cell membranes |
| GO:0004623 A2-type glycerophospholipase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Phospholipase A2 activity reported for recombinant iPLA2-zeta/PEDF-R in vitro, stimulated by PEDF binding in the retinal PEDF-receptor model. The activity is real in the assays described but is minor relative to triacylglycerol hydrolysis and has not been connected to the lipid-droplet lipolysis function or to the NLSDM phenotype. Reason: Experimentally supported in vitro side activity; retained but not part of the core triacylglycerol-lipase function. Supporting Evidence: PMID:17032652 PEDF binding stimulates the enzymatic phospholipase A(2) activity of PEDF-R. PMID:17032652 has a potent phospholipase A(2) activity that liberates fatty acids, and is associated with eukaryotic cell membranes |
| GO:0004806 triacylglycerol lipase activity | EXP PMID:17603008 A comparative study of human GS2, its paralogues, and its ra... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:17603008 Only hGS2 and hTTS-2.2 transfer fatty acid from triglyceride to retinol, hydrolyze retinylesters, and generate 1,3-diacylglycerol from triglycerides. file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | IDA PMID:15364929 Identification, cloning, expression, and purification of thr... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15364929 we demonstrate that each possesses abundant TAG lipase activity |
| GO:0004806 triacylglycerol lipase activity | IDA PMID:15550674 Fat mobilization in adipose tissue is promoted by adipose tr... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:15550674 It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. |
| GO:0004806 triacylglycerol lipase activity | IDA PMID:16150821 Expression, regulation, and triglyceride hydrolase activity ... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:16150821 All four proteins show lipase activity in vitro, which is dependent on the presence of the active site serine for Adiponutrin, Desnutrin/ATGL, and GS2. |
| GO:0004806 triacylglycerol lipase activity | IDA PMID:17603008 A comparative study of human GS2, its paralogues, and its ra... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:17603008 Only hGS2 and hTTS-2.2 transfer fatty acid from triglyceride to retinol, hydrolyze retinylesters, and generate 1,3-diacylglycerol from triglycerides. file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | IDA PMID:34903883 Peroxisomal Ξ²-oxidation acts as a sensor for intracellular f... | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis |
| GO:0004806 triacylglycerol lipase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | IMP PMID:16239926 ATGL has a key role in lipid droplet/adiposome degradation i... | ACCEPT | Summary: Loss/catalytic-dead experiments in mammalian cells show ATGL catalytic activity is required for triacylglycerol and lipid droplet turnover. Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:16239926 Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0004806 triacylglycerol lipase activity | TAS Reactome:R-HSA-1482777 | ACCEPT | Summary: Triacylglycerol lipase activity is the defining catalytic function of ATGL/PNPLA2: it hydrolyzes the first ester bond of stored triacylglycerol on cytoplasmic lipid droplets, producing diacylglycerol and a fatty acid. Reason: Core molecular function, supported by purified human enzyme assays, active-site serine dependence and cellular loss-of-function data; biallelic loss causes neutral lipid storage disease with myopathy. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis file:human/PNPLA2/PNPLA2-uniprot.txt Catalyzes the initial step in triglyceride hydrolysis in |
| GO:0005515 protein binding | IPI PMID:17032652 Identification of a lipase-linked cell membrane receptor for... | REMOVE | Summary: Bare protein binding from the yeast two-hybrid identification of PNPLA2 as a binding partner of pigment epithelium-derived factor (SERPINF1/PEDF). Reason: Protein binding carries no functional information. The PEDF interaction is recorded in the PEDF-R literature, but no more informative, well-established molecular function term follows from this screen; removal does not mean the interaction is false. Supporting Evidence: PMID:17032652 PEDF binding stimulates the enzymatic phospholipase A(2) activity of PEDF-R. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytoplasm. ATGL is a cytoplasmic protein that acts on cytoplasmic lipid droplets; the cytoplasm term is correct but less informative than lipid droplet. Reason: Correct but general location; lipid droplet is the functionally relevant compartment. Supporting Evidence: file:human/PNPLA2/PNPLA2-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:Q8BJ56} file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytoplasm. ATGL is a cytoplasmic protein that acts on cytoplasmic lipid droplets; the cytoplasm term is correct but less informative than lipid droplet. Reason: Correct but general location; lipid droplet is the functionally relevant compartment. Supporting Evidence: file:human/PNPLA2/PNPLA2-uniprot.txt Cytoplasm {ECO:0000250|UniProtKB:Q8BJ56} file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | REMOVE | Summary: Endoplasmic reticulum lumen, from the Reactome reaction listing PNPLA2 among the substrates of the secretory-pathway kinase FAM20C. Reason: ATGL is a cytosolic, lipid-droplet- and ER-surface-associated enzyme with no evidence of luminal residence; the location is an artefact of a bulk Reactome substrate list rather than a demonstrated localization. Supporting Evidence: Reactome:R-HSA-8952289 Extracellular serine/threonine protein kinase FAM20C is an extracellular kinase that can phosphorylate a broad range of secreted protein. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482647 | KEEP AS NON CORE | Summary: ER membrane from Reactome reactions that place PNPLA2/3-mediated acylglycerol hydrolysis and transacylation at the ER membrane. ATGL can associate with ER membranes, but its primary experimentally demonstrated site of action is the lipid droplet surface. Reason: Plausible secondary location; the core location is lipid droplet. Supporting Evidence: Reactome:R-HSA-1482811 patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG) file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482654 | KEEP AS NON CORE | Summary: ER membrane from Reactome reactions that place PNPLA2/3-mediated acylglycerol hydrolysis and transacylation at the ER membrane. ATGL can associate with ER membranes, but its primary experimentally demonstrated site of action is the lipid droplet surface. Reason: Plausible secondary location; the core location is lipid droplet. Supporting Evidence: Reactome:R-HSA-1482811 patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG) file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482777 | KEEP AS NON CORE | Summary: ER membrane from Reactome reactions that place PNPLA2/3-mediated acylglycerol hydrolysis and transacylation at the ER membrane. ATGL can associate with ER membranes, but its primary experimentally demonstrated site of action is the lipid droplet surface. Reason: Plausible secondary location; the core location is lipid droplet. Supporting Evidence: Reactome:R-HSA-1482811 patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG) file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482811 | KEEP AS NON CORE | Summary: ER membrane from Reactome reactions that place PNPLA2/3-mediated acylglycerol hydrolysis and transacylation at the ER membrane. ATGL can associate with ER membranes, but its primary experimentally demonstrated site of action is the lipid droplet surface. Reason: Plausible secondary location; the core location is lipid droplet. Supporting Evidence: Reactome:R-HSA-1482811 patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG) file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IBA GO_REF:0000033 | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: PMID:15550674 It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IDA GO_REF:0000052 | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: PMID:15550674 It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IDA PMID:16239926 ATGL has a key role in lipid droplet/adiposome degradation i... | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: PMID:16239926 Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IDA PMID:21498505 Human lysophosphatidylcholine acyltransferases 1 and 2 are l... | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IDA PMID:28578400 Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fu... | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: PMID:28578400 Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IDA PMID:34903883 Peroxisomal Ξ²-oxidation acts as a sensor for intracellular f... | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005811 lipid droplet | IEA GO_REF:0000120 | ACCEPT | Summary: Lipid droplet. ATGL localizes to cytoplasmic lipid droplets, where it hydrolyzes stored triacylglycerol; a catalytically inactive mutant still targets droplets. Reason: Core location supported by multiple independent localization studies. Supporting Evidence: PMID:15550674 It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. file:human/PNPLA2/PNPLA2-uniprot.txt Lipid droplet {ECO:0000269|PubMed:16239926, |
| GO:0005886 plasma membrane | IDA PMID:17032652 Identification of a lipase-linked cell membrane receptor for... | KEEP AS NON CORE | Summary: Plasma membrane, from the PEDF-R study in which recombinant PNPLA2 was associated with cell membranes in retinal pigment epithelium-derived systems. Reason: Experimentally reported in the PEDF-receptor context; not the location of the core lipid-droplet lipase function. Supporting Evidence: PMID:17032652 has a potent phospholipase A(2) activity that liberates fatty acids, and is associated with eukaryotic cell membranes file:human/PNPLA2/PNPLA2-uniprot.txt Cell CC membrane {ECO:0000269|PubMed:17032652} |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane, from the PEDF-R study in which recombinant PNPLA2 was associated with cell membranes in retinal pigment epithelium-derived systems. Reason: Experimentally reported in the PEDF-receptor context; not the location of the core lipid-droplet lipase function. Supporting Evidence: PMID:17032652 has a potent phospholipase A(2) activity that liberates fatty acids, and is associated with eukaryotic cell membranes file:human/PNPLA2/PNPLA2-uniprot.txt Cell CC membrane {ECO:0000269|PubMed:17032652} |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: General InterPro-derived lipid metabolic process. Reason: Correct but uninformative; the specific process is triglyceride catabolism. Proposed replacements: triglyceride catabolic process Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis |
| GO:0006651 diacylglycerol biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Diacylglycerol biosynthetic process, by orthology. Hydrolysis of triacylglycerol by ATGL produces diacylglycerol, and in vitro transacylation can generate diacylglycerol, but ATGL acts catabolically; diacylglycerol is an intermediate of lipolysis rather than a biosynthetic end product here. Reason: Technically correct product-level description, but the physiological role is triglyceride catabolism. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0010898 positive regulation of triglyceride catabolic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-derived positive regulation of triglyceride catabolic process. ATGL is the catalyst of triglyceride hydrolysis rather than a regulator of it; the regulatory term properly belongs to activators such as ABHD5/CGI-58. Reason: The gene product performs the catabolic step, so the direct process term is appropriate. Proposed replacements: triglyceride catabolic process Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:16679289 CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. |
| GO:0016042 lipid catabolic process | IEA GO_REF:0000002 | MODIFY | Summary: General InterPro-derived lipid catabolic process. Reason: Correct but uninformative; the specific catabolic process is triglyceride catabolism. Proposed replacements: triglyceride catabolic process Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis |
| GO:0016411 acylglycerol O-acyltransferase activity | IDA PMID:17603008 A comparative study of human GS2, its paralogues, and its ra... | KEEP AS NON CORE | Summary: Acylglycerol O-acyltransferase (transacylase) activity. Purified human ATGL transfers acyl chains between acylglycerols in vitro, and recombinant ATGL transacylation generates FAHFAs from triglyceride-derived acyl chains. Reason: Experimentally supported secondary activity; the physiological weight relative to lipolysis is still being defined. Supporting Evidence: PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor PMID:35676490 recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs |
| GO:0016411 acylglycerol O-acyltransferase activity | TAS Reactome:R-HSA-1482647 | KEEP AS NON CORE | Summary: Acylglycerol O-acyltransferase (transacylase) activity. Purified human ATGL transfers acyl chains between acylglycerols in vitro, and recombinant ATGL transacylation generates FAHFAs from triglyceride-derived acyl chains. Reason: Experimentally supported secondary activity; the physiological weight relative to lipolysis is still being defined. Supporting Evidence: Reactome:R-HSA-1482883 Acyl chain remodeling of triacylglycerol (TAG) and diacylglycerol (DAG) progresses PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0016411 acylglycerol O-acyltransferase activity | TAS Reactome:R-HSA-1482654 | KEEP AS NON CORE | Summary: Acylglycerol O-acyltransferase (transacylase) activity. Purified human ATGL transfers acyl chains between acylglycerols in vitro, and recombinant ATGL transacylation generates FAHFAs from triglyceride-derived acyl chains. Reason: Experimentally supported secondary activity; the physiological weight relative to lipolysis is still being defined. Supporting Evidence: Reactome:R-HSA-1482883 Acyl chain remodeling of triacylglycerol (TAG) and diacylglycerol (DAG) progresses PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic hydrolase activity from InterPro. Reason: Correct but uninformative; the specific activity is triacylglycerol lipase activity. Proposed replacements: triacylglycerol lipase activity Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis |
| GO:0019433 triglyceride catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Triglyceride catabolic process. ATGL catalyzes the first, rate-limiting step of intracellular triacylglycerol breakdown; loss of ATGL blocks triglyceride degradation and causes neutral lipid storage disease with myopathy. Reason: Core biological process, directly performed by the gene product. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:16150821 Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. PMID:17187067 The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. |
| GO:0019433 triglyceride catabolic process | IDA PMID:16679289 Adipose triglyceride lipase-mediated lipolysis of cellular f... | ACCEPT | Summary: Triglyceride catabolic process. ATGL catalyzes the first, rate-limiting step of intracellular triacylglycerol breakdown; loss of ATGL blocks triglyceride degradation and causes neutral lipid storage disease with myopathy. Reason: Core biological process, directly performed by the gene product. Supporting Evidence: PMID:16679289 CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. PMID:17187067 The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. |
| GO:0019433 triglyceride catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Triglyceride catabolic process. ATGL catalyzes the first, rate-limiting step of intracellular triacylglycerol breakdown; loss of ATGL blocks triglyceride degradation and causes neutral lipid storage disease with myopathy. Reason: Core biological process, directly performed by the gene product. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:16150821 Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. PMID:17187067 The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. |
| GO:0019433 triglyceride catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Triglyceride catabolic process. ATGL catalyzes the first, rate-limiting step of intracellular triacylglycerol breakdown; loss of ATGL blocks triglyceride degradation and causes neutral lipid storage disease with myopathy. Reason: Core biological process, directly performed by the gene product. Supporting Evidence: PMID:15550674 a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis PMID:16150821 Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. PMID:17187067 The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. |
| GO:0034389 lipid droplet organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Lipid droplet organization. ATGL controls lipid droplet size and turnover through triacylglycerol hydrolysis. Reason: Consequence of the core lipase activity; captured more specifically by lipid droplet disassembly. Supporting Evidence: PMID:16239926 Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. PMID:16239926 Depletion of ATGL by RNA interference leads to a significant increase in the size of LDs. |
| GO:0034389 lipid droplet organization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Lipid droplet organization. ATGL controls lipid droplet size and turnover through triacylglycerol hydrolysis. Reason: Consequence of the core lipase activity; captured more specifically by lipid droplet disassembly. Supporting Evidence: PMID:16239926 Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. PMID:16239926 Depletion of ATGL by RNA interference leads to a significant increase in the size of LDs. |
| GO:0035356 intracellular triglyceride homeostasis | IMP PMID:28578400 Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fu... | KEEP AS NON CORE | Summary: Intracellular triglyceride homeostasis, from LDAH/ATGL counterbalancing experiments. Reason: Correct downstream consequence of lipolysis; core process is triglyceride catabolism. Supporting Evidence: PMID:28578400 Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. |
| GO:0036155 acylglycerol acyl-chain remodeling | TAS Reactome:R-HSA-1482883 | KEEP AS NON CORE | Summary: Acylglycerol acyl-chain remodeling (Reactome), the cycle in which PNPLA2/3 hydrolysis and transacylation exchange acyl chains of DAG and TAG. Reason: Reactome pathway inference built from the in vitro transacylase activity; not a demonstrated core process in cells. Supporting Evidence: Reactome:R-HSA-1482883 Acyl chain remodeling of triacylglycerol (TAG) and diacylglycerol (DAG) progresses PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0042572 retinol metabolic process | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Retinol metabolic process, inferred from retinyl ester hydrolase activity. Reason: Retinyl ester hydrolysis by TTS-2.2/ATGL is reported in vitro; physiological retinoid metabolism by ATGL is not established. Supporting Evidence: PMID:17603008 Only hGS2 and hTTS-2.2 transfer fatty acid from triglyceride to retinol, hydrolyze retinylesters, and generate 1,3-diacylglycerol from triglycerides. file:human/PNPLA2/PNPLA2-deep-research-falcon.md essentially no monoacylglycerol, cholesteryl-ester, or retinyl-ester hydrolysis |
| GO:0050253 retinyl-palmitate esterase activity | EXP PMID:17603008 A comparative study of human GS2, its paralogues, and its ra... | KEEP AS NON CORE | Summary: Retinyl-palmitate esterase activity. Human TTS-2.2 (PNPLA2) hydrolyzed retinyl esters in a comparative study of the GS2 paralog family. Reason: Experimentally reported side activity; not part of the core triacylglycerol-lipase function. Supporting Evidence: PMID:17603008 Only hGS2 and hTTS-2.2 transfer fatty acid from triglyceride to retinol, hydrolyze retinylesters, and generate 1,3-diacylglycerol from triglycerides. file:human/PNPLA2/PNPLA2-uniprot.txt triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3- file:human/PNPLA2/PNPLA2-deep-research-falcon.md essentially no monoacylglycerol, cholesteryl-ester, or retinyl-ester hydrolysis |
| GO:0050253 retinyl-palmitate esterase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Retinyl-palmitate esterase activity. Human TTS-2.2 (PNPLA2) hydrolyzed retinyl esters in a comparative study of the GS2 paralog family. Reason: Experimentally reported side activity; not part of the core triacylglycerol-lipase function. Supporting Evidence: PMID:17603008 Only hGS2 and hTTS-2.2 transfer fatty acid from triglyceride to retinol, hydrolyze retinylesters, and generate 1,3-diacylglycerol from triglycerides. file:human/PNPLA2/PNPLA2-uniprot.txt triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3- file:human/PNPLA2/PNPLA2-deep-research-falcon.md essentially no monoacylglycerol, cholesteryl-ester, or retinyl-ester hydrolysis |
| GO:0051264 mono-olein transacylation activity | IDA PMID:15364929 Identification, cloning, expression, and purification of thr... | KEEP AS NON CORE | Summary: Mono-olein transacylation activity of purified recombinant human iPLA2-zeta. Reason: In vitro transacylase activity; secondary to triacylglycerol hydrolysis. Supporting Evidence: PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0051265 diolein transacylation activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Diolein transacylation activity of purified recombinant human iPLA2-zeta (and by phylogenetic inference). Reason: In vitro transacylase activity; secondary to triacylglycerol hydrolysis. Supporting Evidence: PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0051265 diolein transacylation activity | IDA PMID:15364929 Identification, cloning, expression, and purification of thr... | KEEP AS NON CORE | Summary: Diolein transacylation activity of purified recombinant human iPLA2-zeta (and by phylogenetic inference). Reason: In vitro transacylase activity; secondary to triacylglycerol hydrolysis. Supporting Evidence: PMID:15364929 also possess acylglycerol transacylase activity utilizing mono-olein as an acyl donor |
| GO:0055088 lipid homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Lipid homeostasis (phylogenetic inference). ATGL-mediated lipolysis contributes to cellular lipid homeostasis. Reason: Correct high-level process; the specific core process is triglyceride catabolism. Supporting Evidence: PMID:16150821 Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. PMID:28578400 Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. |
| GO:0160077 lipid droplet fusion | IDA PMID:28578400 Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fu... | KEEP AS NON CORE | Summary: Lipid droplet fusion with the qualifier acts_upstream_of_negative_effect: ATGL counteracts LDAH-induced lipid droplet coalescence in co-expression experiments. Reason: Supported by the cited co-expression data and correctly qualified as a negative effect; it is a consequence of lipolysis rather than a core activity. Supporting Evidence: PMID:28578400 Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. |
| GO:1905691 lipid droplet disassembly | IMP PMID:16239926 ATGL has a key role in lipid droplet/adiposome degradation i... | ACCEPT | Summary: Lipid droplet disassembly. RNAi depletion of ATGL enlarges lipid droplets and wild-type but not catalytically inactive ATGL shrinks them, so ATGL catalysis drives droplet turnover. Reason: Direct cellular consequence of ATGL triacylglycerol hydrolysis on the droplet; supported by loss- and gain-of-function data. Supporting Evidence: PMID:16239926 Overexpression of wild-type ATGL causes a marked decrease in LD size, whereas a catalytically inactive mutant retains the ability to localize to LDs, but is unable to decrease their size. PMID:16239926 Depletion of ATGL by RNA interference leads to a significant increase in the size of LDs. file:human/PNPLA2/PNPLA2-uniprot.txt Regulates CC adiposome size and may be involved in the degradation of adiposomes |
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Download this section (compressed HTML)Q: How much of ATGL-dependent FAHFA synthesis and acylglycerol transacylation occurs in human adipose tissue relative to its lipase flux, and should a FAHFA biosynthetic process annotation be added?
Q: Is the PEDF-R plasma-membrane receptor model of PNPLA2 compatible with its lipid-droplet localization, or does it reflect a distinct pool or isoform?
Experiment: Quantify the residual triacylglycerol hydrolase and transacylase activities of NLSDM patient missense and C-terminally truncated ATGL variants in purified form with and without ABHD5, to separate catalytic loss from loss of lipid-droplet targeting.
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