LIPA encodes lysosomal acid lipase (LAL; cholesteryl ester hydrolase, EC 3.1.1.13), a glycosylated serine hydrolase of the acid lipase family that is synthesized as a preproprotein and acts in the lysosomal lumen at acid pH. It hydrolyzes cholesteryl esters and triacylglycerols, and also diacylglycerols, delivered to lysosomes by receptor-mediated endocytosis of low-density lipoproteins, releasing free cholesterol and fatty acids for use by the cell. Biallelic loss-of-function variants cause lysosomal acid lipase deficiency, which ranges from infantile-onset Wolman disease, with no residual activity, to the milder cholesteryl ester storage disease, in which residual activity remains.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004771 sterol ester esterase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins file:human/LIPA/LIPA-uniprot.txt Catalyzes the deacylation of cholesteryl ester core lipids of |
| GO:0004771 sterol ester esterase activity | IDA PMID:15269241 Lysosomal acid lipase as a preproprotein. | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:15269241 Lysosomal acid lipase (LAL; EC 3.1.1.13) hydrolyzes intracellular triglycerides and cholesterol esters taken up by various cell-types. |
| GO:0004771 sterol ester esterase activity | IDA PMID:1718995 Cloning and expression of cDNA encoding human lysosomal acid... | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:1718995 Transfection of the cDNA into Cos-1 cells resulted in the expression of acid lipase activity with the substrate range of the native enzyme |
| GO:0004771 sterol ester esterase activity | IDA PMID:7204383 Purification of the lysosomal acid lipase from human liver a... | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme PMID:7204383 The recoveries of both trioleoylglycerol and cholesterol oleate hydrolytic activities were nearly identical at each purification step |
| GO:0004771 sterol ester esterase activity | IDA PMID:8112342 Purification, characterization and molecular cloning of huma... | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:8112342 When assayed in the presence of cholesteryl oleate or trioleoylglycerol, purified acid lipase had Vmax values |
| GO:0004771 sterol ester esterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins file:human/LIPA/LIPA-uniprot.txt Catalyzes the deacylation of cholesteryl ester core lipids of |
| GO:0004771 sterol ester esterase activity | IMP PMID:9633819 Different missense mutations in histidine-108 of lysosomal a... | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: PMID:9633819 Expression of the LAL enzymes with the His108-->Pro and His108-->Arg mutation in insect cells revealed residual enzymatic activities of 4.6% versus 2.7%, respectively, compared with controls. PMID:9633819 WD is caused by genetic defects of LAL that leave no residual enzymatic activity, while in CESD patients a residual LAL activity can be identified. |
| GO:0004771 sterol ester esterase activity | TAS Reactome:R-HSA-8865667 | ACCEPT | Summary: Sterol (cholesteryl) ester esterase activity. Purified and recombinant human LAL hydrolyzes cholesteryl esters delivered to the lysosome; loss of this activity causes Wolman disease and cholesteryl ester storage disease. Reason: Core molecular function supported by purification, heterologous expression and disease-variant studies. Supporting Evidence: Reactome:R-HSA-8865667 catalyses the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins |
| GO:0004806 triacylglycerol lipase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Triacylglycerol lipase activity. Purified human liver LAL hydrolyzes trioleoylglycerol with kinetics comparable to cholesteryl oleate, and both activities co-purify as a single enzyme. Reason: Core molecular function alongside cholesteryl ester hydrolysis; experimentally supported. Supporting Evidence: PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme PMID:7204383 The recoveries of both trioleoylglycerol and cholesterol oleate hydrolytic activities were nearly identical at each purification step PMID:8112342 When assayed in the presence of cholesteryl oleate or trioleoylglycerol, purified acid lipase had Vmax values |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Lysosome. LAL is the lysosomal acid lipase: it acts at acid pH on lipids delivered to lysosomes by endocytosis. Reason: Core location; the enzyme is defined by lysosomal action. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:8112342 The purified enzyme was most active at low pH (4.5-5.0) file:human/LIPA/LIPA-uniprot.txt Lysosome {ECO:0000250|UniProtKB:Q64194} |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: Lysosome. LAL is the lysosomal acid lipase: it acts at acid pH on lipids delivered to lysosomes by endocytosis. Reason: Core location; the enzyme is defined by lysosomal action. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:8112342 The purified enzyme was most active at low pH (4.5-5.0) file:human/LIPA/LIPA-uniprot.txt Lysosome {ECO:0000250|UniProtKB:Q64194} |
| GO:0005764 lysosome | TAS PMID:1718995 Cloning and expression of cDNA encoding human lysosomal acid... | ACCEPT | Summary: Lysosome. LAL is the lysosomal acid lipase: it acts at acid pH on lipids delivered to lysosomes by endocytosis. Reason: Core location; the enzyme is defined by lysosomal action. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:8112342 The purified enzyme was most active at low pH (4.5-5.0) file:human/LIPA/LIPA-uniprot.txt Lysosome {ECO:0000250|UniProtKB:Q64194} |
| GO:0016125 sterol metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Sterol metabolic process (phylogenetic inference). LAL hydrolysis of cholesteryl esters releases free cholesterol from endocytosed lipoproteins. Reason: Correct process, consistent with the core cholesteryl ester hydrolase activity. Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins file:human/LIPA/LIPA-uniprot.txt Catalyzes the deacylation of cholesteryl ester core lipids of |
| GO:0016298 lipase activity | IDA PMID:1718995 Cloning and expression of cDNA encoding human lysosomal acid... | MODIFY | Summary: Generic lipase activity. Correct, but the specific activities are sterol ester esterase and triacylglycerol lipase activity. Reason: Replace the general parent term with the specific triacylglycerol lipase activity (cholesteryl ester hydrolysis is captured separately by GO:0004771). Proposed replacements: triacylglycerol lipase activity Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme |
| GO:0016298 lipase activity | IEA GO_REF:0000117 | MODIFY | Summary: Generic lipase activity. Correct, but the specific activities are sterol ester esterase and triacylglycerol lipase activity. Reason: Replace the general parent term with the specific triacylglycerol lipase activity (cholesteryl ester hydrolysis is captured separately by GO:0004771). Proposed replacements: triacylglycerol lipase activity Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme |
| GO:0016788 hydrolase activity, acting on ester bonds | IEA GO_REF:0000002 | MODIFY | Summary: Generic hydrolase activity acting on ester bonds, from InterPro. Reason: Correct but uninformative; the specific activity is sterol ester esterase activity. Proposed replacements: sterol ester esterase activity Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins |
| GO:0034383 low-density lipoprotein particle clearance | TAS Reactome:R-HSA-8964038 | KEEP AS NON CORE | Summary: Low-density lipoprotein particle clearance (Reactome). LAL hydrolyzes the core lipids of LDL particles after receptor-mediated endocytosis and lysosomal delivery; the clearance process itself is driven by LDL receptor uptake. Reason: LAL performs the lysosomal degradation step of LDL core lipids within the clearance pathway, but not uptake; retained as a non-core pathway context. Supporting Evidence: Reactome:R-HSA-8964038 The LDL particles move into lysosomes and are degraded while the LDL receptors are returned to the cell surface. PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-8865667 | ACCEPT | Summary: Lysosomal lumen, where LAL hydrolyzes cholesteryl ester and triacylglycerol cores of endocytosed lipoproteins. Reason: Correct, more specific core location. Supporting Evidence: Reactome:R-HSA-8865667 catalyses the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:8112342 The purified enzyme was most active at low pH (4.5-5.0) |
| GO:0052689 carboxylic ester hydrolase activity | IEA GO_REF:0000117 | MODIFY | Summary: Generic carboxylic ester hydrolase activity, from ARBA. Reason: Correct but uninformative; the specific activity is sterol ester esterase activity. Proposed replacements: sterol ester esterase activity Supporting Evidence: PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins |
| GO:0120516 diacylglycerol lipase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Diacylglycerol lipase activity. Purified LAL hydrolyzes 1,2- and 1,3-dioleoylglycerols with high apparent Vmax. Reason: Experimentally supported; diacylglycerol hydrolysis is part of the stepwise breakdown of lysosomal triacylglycerol but is secondary to the cholesteryl ester and triacylglycerol activities. Supporting Evidence: PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme file:human/LIPA/LIPA-uniprot.txt diacylglycerol) with preference for the acyl moieties at the sn-1 or |
| GO:0019433 triglyceride catabolic process | IDA PMID:7204383 Purification of the lysosomal acid lipase from human liver a... | NEW | Summary: Proposed process not currently in GOA. LAL is the lysosomal enzyme that hydrolyzes the triacylglycerol delivered to lysosomes, and purified enzyme hydrolyzes trioleoylglycerol and both dioleoylglycerol isomers. Reason: Direct catalytic participation in triacylglycerol breakdown, supported by purified-enzyme kinetics; loss causes lysosomal neutral lipid storage in Wolman disease and CESD. This replaces an earlier proposal of GO:0046461 neutral lipid catabolic process, which is an ancestor of this term and of nothing else LIPA needs, since the cholesteryl ester half of the same reaction is proposed separately as GO:0090122; the general neutral-lipid term would have added only redundancy. Supporting Evidence: PMID:7204383 suggesting that the acid lipase as single enzyme is responsible for lysosomal hydrolysis of PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins |
| GO:0090122 cholesterol ester hydrolysis involved in cholesterol transport | IDA PMID:7204383 Purification of the lysosomal acid lipase from human liver a... | NEW | Summary: Proposed process not currently in GOA for LIPA. The GO definition (cholesterol esters hydrolyzed into free fatty acids and cholesterol in the lysosome, contributing to intracellular cholesterol transport) describes exactly the LAL reaction on endocytosed LDL cholesteryl esters, and the purified enzyme hydrolyzes cholesterol oleate directly. Reason: LAL is the enzyme that performs the lysosomal cholesteryl ester hydrolysis step that this term names; the only current GOA annotation is CES1 by TAS. The evidence is direct assay on the purified enzyme, which gives a Vmax and Km for cholesterol oleate, so this row takes IDA from PMID:7204383 rather than TAS from a review sentence - the same basis as its GO:0019433 sibling, which is the triacylglycerol half of the same purification. Supporting Evidence: PMID:7204383 Trioleoylglycerol, cholesterol oleate, and 1,2- and 1,3-dioleoylglycerols were substrates for the purified enzyme giving apparent Vmax values PMID:1718995 The lysosomal enzyme catalyzes the deacylation of triacylglyceryl and cholesteryl ester core lipids of endocytosed low density lipoproteins PMID:15269241 Lysosomal acid lipase (LAL; EC 3.1.1.13) hydrolyzes intracellular triglycerides and cholesterol esters taken up by various cell-types. |
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Download this section (compressed HTML)Q: GO:0090122 (cholesterol ester hydrolysis involved in cholesterol transport) is proposed here as a NEW annotation for LIPA, since its definition names the lysosomal step LAL performs. Its only current annotation is CES1 by TAS, and CES1 is a cytosolic/ER enzyme rather than a lysosomal one. Is the CES1 annotation intended, or should the term be understood as naming the lysosomal reaction alone?
Experiment: Measure residual cholesteryl ester and triacylglycerol hydrolase activities of a panel of CESD and Wolman missense LIPA variants expressed in a common system, to test whether the two activities are lost in parallel or can be dissociated.
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