LIPE encodes hormone-sensitive lipase (HSL), an intracellular neutral-lipid serine hydrolase that is recruited from the cytosol to lipid droplets during stimulated lipolysis. Its best-supported core catalytic role is hydrolysis of diacylglycerol to monoacylglycerol and fatty acid in the adipocyte lipolysis cascade; it also hydrolyzes other neutral esters, including triacylglycerols, cholesteryl esters, monoacylglycerols, and retinyl esters in tissue-specific contexts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0004771
sterol ester esterase activity
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate activity rather than the central adipocyte DAG-lipase role.
Reason: sterol ester esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
PMID:15716583
Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for adrenal steroidogenesis.
|
|
GO:0004806
triacylglycerol lipase activity
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
Reason: triacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0005829
cytosol
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The cytosol annotation is consistent with basal HSL localization before stimulated lipid-droplet recruitment.
Reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0019433
triglyceride catabolic process
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: HSL acts within the canonical triglyceride catabolic cascade by hydrolyzing DAG produced from TAG.
Reason: triglyceride catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0042572
retinol metabolic process
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Retinol metabolism is supported by recent physiology but is a tissue/context-specific secondary role rather than the primary neutral-lipid lipolysis function.
Reason: retinol metabolic process is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In 2024, adipocyte HSL was shown to be required for maintenance of circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A role.
|
|
GO:0004771
sterol ester esterase activity
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate activity rather than the central adipocyte DAG-lipase role.
Reason: sterol ester esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
PMID:15716583
Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for adrenal steroidogenesis.
|
|
GO:0004806
triacylglycerol lipase activity
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
Reason: triacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0005811
lipid droplet
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: The lipid droplet annotation captures the regulated site where HSL gains access to stored neutral lipid substrates.
Reason: lipid droplet is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0005829
cytosol
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: The cytosol annotation is consistent with basal HSL localization before stimulated lipid-droplet recruitment.
Reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Plasma membrane association has experimental support through PTRF/caveola studies, but it is not the main functional location of HSL.
Reason: plasma membrane is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
PMID:17026959
In the plasma membrane PTRF was specifically bound to a triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase (HSL).
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0005901
caveola
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Caveola association is supported in adipocytes through PTRF, but it is secondary to cytosol-to-lipid-droplet recruitment during lipolysis.
Reason: caveola is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
PMID:17026959
In the plasma membrane PTRF was specifically bound to a triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase (HSL).
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0006629
lipid metabolic process
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The generic lipid metabolic process annotation is directionally correct but too broad for HSL. Lipid catabolic process, and more specifically diacylglycerol catabolic process, better capture the reviewed function.
Reason: lipid metabolic process is less informative than the reviewed LIPE/HSL lipolysis term.
Proposed replacements:
lipid catabolic process
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0008202
steroid metabolic process
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: Steroid metabolic process is plausible through cholesteryl ester hydrolysis in steroidogenic tissues but is not the central LIPE function.
Reason: steroid metabolic process is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
PMID:15716583
Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for adrenal steroidogenesis.
|
|
GO:0008203
cholesterol metabolic process
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Cholesterol metabolism is supported through cholesteryl ester hydrolysis, but this is a secondary substrate context.
Reason: cholesterol metabolic process is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
PMID:15716583
The relatively higher turnover of HSL on CO observed in vitro adds further molecular insight on the physiological importance of HSL in cholesteryl ester catabolism in vivo.
|
|
GO:0016042
lipid catabolic process
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Lipid catabolic process is supported because LIPE/HSL hydrolyzes neutral lipid esters during lipolysis.
Reason: lipid catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0016298
lipase activity
|
IEA
GO_REF:0000002 |
MODIFY |
Summary: Generic lipase activity should be refined to diacylglycerol lipase activity because DAG hydrolysis is the best-supported core catalytic step.
Reason: lipase activity is less informative than the reviewed LIPE/HSL lipolysis term.
Proposed replacements:
diacylglycerol lipase activity
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0016787
hydrolase activity
|
IEA
GO_REF:0000120 |
MODIFY |
Summary: Generic hydrolase activity obscures the specific serine-lipase reaction supported for LIPE/HSL.
Reason: hydrolase activity is less informative than the reviewed LIPE/HSL lipolysis term.
Proposed replacements:
diacylglycerol lipase activity
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0047372
monoacylglycerol lipase activity
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Monoacylglycerol lipase activity is consistent with broad HSL substrate specificity, but the dominant physiological lipolysis role is DAG hydrolysis.
Reason: monoacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0047376
all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity
|
IEA
GO_REF:0000116 |
KEEP AS NON CORE |
Summary: Retinyl-palmitate hydrolase activity is supported as part of retinoid mobilization but should be treated as a secondary substrate-specific function.
Reason: all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In 2024, adipocyte HSL was shown to be required for maintenance of circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A role.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0050253
retinyl-palmitate esterase activity
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Retinyl-palmitate esterase activity is supported as part of retinoid mobilization but is secondary to the primary DAG lipase role.
Reason: retinyl-palmitate esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In 2024, adipocyte HSL was shown to be required for maintenance of circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A role.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0120516
diacylglycerol lipase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
Reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Protein binding is too generic for curation of LIPE; the reviewed biology is better represented by regulated localization to PLIN1-coated lipid droplets and specific lipid hydrolase activities.
Reason: protein binding overstates or obscures the specific supported LIPE function.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: The cytosol annotation is consistent with basal HSL localization before stimulated lipid-droplet recruitment.
Reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0019433
triglyceride catabolic process
|
IEA
GO_REF:0000041 |
ACCEPT |
Summary: HSL acts within the canonical triglyceride catabolic cascade by hydrolyzing DAG produced from TAG.
Reason: triglyceride catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0004771
sterol ester esterase activity
|
IDA
PMID:15716583 Continuous monitoring of cholesterol oleate hydrolysis by ho... |
KEEP AS NON CORE |
Summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate activity rather than the central adipocyte DAG-lipase role.
Reason: sterol ester esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
PMID:15716583
Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for adrenal steroidogenesis.
|
|
GO:0004771
sterol ester esterase activity
|
IDA
PMID:8812477 Molecular cloning, genomic organization, and expression of a... |
KEEP AS NON CORE |
Summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate activity rather than the central adipocyte DAG-lipase role.
Reason: sterol ester esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
PMID:15716583
Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for adrenal steroidogenesis.
|
|
GO:0004806
triacylglycerol lipase activity
|
IDA
PMID:15716583 Continuous monitoring of cholesterol oleate hydrolysis by ho... |
KEEP AS NON CORE |
Summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
Reason: triacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0004806
triacylglycerol lipase activity
|
IDA
PMID:15955102 Identification of a novel keratinocyte retinyl ester hydrola... |
KEEP AS NON CORE |
Summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
Reason: triacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0016020
membrane
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Generic membrane association is retained as non-core because HSL can associate with caveolae and lipid droplets while remaining primarily a regulated soluble lipase.
Reason: membrane is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
PMID:17026959
In the plasma membrane PTRF was specifically bound to a triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase (HSL).
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0046340
diacylglycerol catabolic process
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Diacylglycerol catabolic process is the most precise biological-process annotation for HSL in the lipolysis cascade.
Reason: diacylglycerol catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
|
|
GO:0046485
ether lipid metabolic process
|
ISS
GO_REF:0000024 |
MARK AS OVER ANNOTATED |
Summary: Ether lipid metabolic process is not supported by the reviewed LIPE literature; the evidence supports neutral acylglycerol, sterol ester, and retinyl ester hydrolysis instead.
Reason: ether lipid metabolic process overstates or obscures the specific supported LIPE function.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0047372
monoacylglycerol lipase activity
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Monoacylglycerol lipase activity is consistent with broad HSL substrate specificity, but the dominant physiological lipolysis role is DAG hydrolysis.
Reason: monoacylglycerol lipase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0050253
retinyl-palmitate esterase activity
|
IDA
PMID:15955102 Identification of a novel keratinocyte retinyl ester hydrola... |
KEEP AS NON CORE |
Summary: Retinyl-palmitate esterase activity is supported as part of retinoid mobilization but is secondary to the primary DAG lipase role.
Reason: retinyl-palmitate esterase activity is supported, but it is secondary to the core DAG-lipase role.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In 2024, adipocyte HSL was shown to be required for maintenance of circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A role.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0120516
diacylglycerol lipase activity
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
Reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0120516
diacylglycerol lipase activity
|
IDA
PMID:19800417 In vitro stereoselective hydrolysis of diacylglycerols by ho... |
ACCEPT |
Summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
Reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0120516
diacylglycerol lipase activity
|
IDA
PMID:8812477 Molecular cloning, genomic organization, and expression of a... |
ACCEPT |
Summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
Reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0005811
lipid droplet
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: The lipid droplet annotation captures the regulated site where HSL gains access to stored neutral lipid substrates.
Reason: lipid droplet is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0016042
lipid catabolic process
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Lipid catabolic process is supported because LIPE/HSL hydrolyzes neutral lipid esters during lipolysis.
Reason: lipid catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is further hydrolyzed by **MAGL** to glycerol and fatty acids.
file:human/LIPE/LIPE-deep-research-falcon.md
HSL has **broad substrate specificity**, with reported activity against **TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
|
|
GO:0005515
protein binding
|
IPI
PMID:17026959 Association and insulin regulated translocation of hormone-s... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is too generic for curation of LIPE; the reviewed biology is better represented by regulated localization to PLIN1-coated lipid droplets and specific lipid hydrolase activities.
Reason: protein binding overstates or obscures the specific supported LIPE function.
Supporting Evidence:
file:human/LIPE/LIPE-deep-research-falcon.md
HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access.
|
|
GO:0006468
protein phosphorylation
|
TAS
PMID:3420405 Hormone-sensitive lipase: sequence, expression, and chromoso... |
REMOVE |
Summary: This annotation treats LIPE as if it performs protein phosphorylation. The cited biology describes HSL as a phosphorylation-regulated lipase, not a kinase.
Reason: LIPE is regulated by phosphorylation but does not catalyze protein phosphorylation.
Supporting Evidence:
PMID:3420405
Hormone-sensitive lipase, a key enzyme in fatty acid mobilization, overall energy homeostasis, and possibly steroidogenesis, is acutely controlled through reversible phosphorylation by catecholamines and insulin.
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The UniProt accession Q05469 corresponds to human hormone‑sensitive lipase (HSL) encoded by LIPE. A recent mechanistic study explicitly states that the “HSL in our study refers to the adipocyte isoform of human HSL (UniProt: Q05469‑2)” and analyzes its structure and lipid‑droplet binding determinants, thereby directly confirming the UniProt→gene/protein mapping for the human target in question. (peng2025moleculardeterminantsfor pages 1-2)
Hormone‑sensitive lipase (HSL) is an intracellular, neutral serine hydrolase central to regulated mobilization of neutral lipids stored in cytosolic lipid droplets (LDs). In adipocytes it functions in hormonally controlled lipolysis, while in other tissues (e.g., steroidogenic) it contributes to mobilization of esterified sterols and other neutral esters. (nagaroor2023anoverviewof pages 4-7, yang2023regulationoflipolysis pages 1-2)
In the canonical LD lipolysis cascade, ATGL (PNPLA2) initiates triacylglycerol (TAG) breakdown to diacylglycerol (DAG), HSL (LIPE) then preferentially hydrolyzes DAG→monoacylglycerol (MAG) + free fatty acid, and MAG is further hydrolyzed by MAGL to glycerol and fatty acids. This stepwise model is summarized in recent reviews and reinforced in human adipocyte‑focused mechanistic literature. (harake2024involvementofa pages 10-12, poursharifi2025glycerolipidcyclingin pages 16-18, yang2023regulationoflipolysis pages 1-2)
HSL has broad substrate specificity, with reported activity against TAG, DAG, MAG, cholesteryl esters, retinyl esters, and other esters; multiple sources emphasize that activity toward DAG is markedly higher than toward TAG, positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase. (nagaroor2023anoverviewof pages 7-10, nagaroor2023anoverviewof pages 4-7, poursharifi2025glycerolipidcyclingin pages 16-18)
Human HSL is a classical serine hydrolase with the catalytic triad Ser424–Asp693–His723 and a conserved GXSXG motif. A 2025 biochemical/structural study validates catalytic Ser424 experimentally: the S424A substitution abolishes enzymatic activity in their assay system. (peng2025moleculardeterminantsfor pages 1-2, nagaroor2023anoverviewof pages 7-10)
A recent recombinant human HSL study reports hydrolysis of p‑nitrophenyl butyrate with Km = 186.1 μM and kcat = 124.5 s−1, providing modern kinetic evidence for catalytic competence of the expressed human enzyme and a benchmark assay used in mechanistic dissection. (peng2025moleculardeterminantsfor pages 1-2)
Cellular localization concept. In adipocytes, HSL is commonly described as largely cytosolic basally and recruited to the lipid droplet surface upon pro‑lipolytic stimulation, where it gains access to neutral lipid substrates within LDs. (yang2023regulationoflipolysis pages 1-2)
Recent structural advance (mechanism of LD binding). A cryo‑EM structure of human HSL (3.4 Å) combined with hydrogen–deuterium exchange MS and cell/biochemical assays identifies two intrinsic LD‑binding motifs:
- residues 489–538, termed the “H‑motif”
- an N‑terminal 4‑helix bundle
Importantly, this work reports that LD binding mediated by these motifs is independent of PKA‑catalyzed phosphorylation, refining (but not negating) the classic phosphorylation/translocation model by separating “intrinsic binding determinants” from “hormonal/PKA regulation.” (peng2025moleculardeterminantsfor pages 1-2)
Figure‑level evidence. The same paper provides figure evidence for (i) overall HSL architecture/organization and (ii) mapping of LD‑binding elements and assay schematics used to test binding to (artificial) lipid droplets. (peng2025moleculardeterminantsfor media 06b3eac4, peng2025moleculardeterminantsfor media 5041a669)
In adipocytes, catecholamine/β‑adrenergic signaling elevates cAMP and activates PKA, which phosphorylates components of the LD lipolysis machinery (notably PLIN1 and HSL) and thereby promotes stimulated lipolysis. A 2024 review emphasizes that PLIN1 phosphorylation recruits HSL to LDs to permit hydrolysis, while PLIN1 dephosphorylation blocks access and inhibits lipolysis. (harake2024involvementofa pages 10-12)
A human adipocyte lipid‑droplet proximity labeling study catalogued PLIN1 interactors and identified LIPE among proteins interacting with PLIN1 on lipid droplets; it also reiterates the canonical model that HSL is phosphorylated by PKA and translocates to LDs to perform hydrolysis, while noting that much mechanistic dogma historically derives from non‑human systems—motivating direct study in human adipocytes. (yang2023regulationoflipolysis pages 1-1, yang2023regulationoflipolysis pages 1-2)
A 2024 Nature study describes oxytocin (OXT) as an endogenous regulator of adipose lipolysis in mice and humans and provides quantitative physiological readouts including ~1.6‑fold increased glycerol release from differentiated mouse adipocytes and a similar effect in human adipose explants. It also distinguishes OXT‑driven lipolysis from the classic PKA route: PKA inhibition blocks isoproterenol‑induced lipolysis but does not affect OXT‑induced lipolysis in their assays, while ERK pathway inhibitors reduce OXT‑induced glycerol release—supporting an ERK‑dependent alternative pathway that converges on lipolysis outputs without necessarily operating through the canonical cAMP/PKA module in the same manner. (li2024controloflipolysis pages 1-5)
HSL is repeatedly positioned as a “core effector” of LD‑based lipolysis in adipocytes, generating fatty acids and glycerol for systemic use during energy demand. (yang2023regulationoflipolysis pages 1-2)
A 2024 EMBO Reports study provides mechanistic physiology linking HSL to systemic retinoid homeostasis: adipocyte HSL is required to maintain circulating retinol and RBP4 during fasting in mice; apo‑RBP4 induces retinol release by adipocytes in an HSL‑dependent manner; and HSL deficiency leads to retinoid accumulation in adipose tissue with a drop in serum retinol and RBP4 and downstream effects in eye and kidney. This supports HSL as a major adipose retinyl ester hydrolase in vivo during fasting. (steinhoff2024adipocytehslis pages 1-2)
Clinical definition and rarity. A 2024 case report notes that familial partial lipodystrophy (FPLD) is rare (~1 in 1,000,000) and underscores genetic testing importance in young patients with severe metabolic syndromes. (zhou2024casereportfirst pages 1-2)
2024 patient report (new variants; concrete phenotype). Zhou et al. (publication month July 2024, URL https://doi.org/10.3389/fgene.2024.1417613) report the first Chinese FPLD6 patient with compound heterozygous LIPE frameshift variants (p.Glu833LysfsTer22 and p.Ser902ThrfsTer27). Reported clinical features include pronounced partial lipodystrophy, hypertriglyceridemia, diabetes mellitus, hepatomegaly/hepatic steatosis, and additional findings (e.g., retinal changes, peripheral neuropathy, renal tubular injury markers). (zhou2024casereportfirst pages 3-5, zhou2024casereportfirst pages 1-2)
Mechanistic interpretation used clinically. The same report explains the mechanistic plausibility: LIPE encodes HSL, which hydrolyzes intracellular triglycerides to free fatty acids in adipose tissue and participates in neutral‑ester hydrolysis in other tissues—linking loss of HSL function to impaired lipid mobilization, fat redistribution, and metabolic complications. (zhou2024casereportfirst pages 1-2)
Synthesis across human reports (review perspective). A 2024 review focused on LD‑pathway genes summarizes that a LIPE null variant was identified in three human subjects with a consistent adult‑onset phenotype including lower‑extremity lipoatrophy, facial/nuchal fat accumulation, insulin resistance/diabetes, hypertriglyceridemia, hepatic steatosis, hypertension, and myopathy; patient‑derived adipose stem cells lacking HSL show impaired adipogenic differentiation, decreased insulin sensitivity, impaired lipolysis, and altered mitochondrial metabolism in the cited work. (harake2024involvementofa pages 12-13, harake2024involvementofa pages 10-12)
Open Targets lists LIPE associations with LIPE‑related familial partial lipodystrophy and familial partial lipodystrophy (Dunnigan type) among other links, and it also reports an association with azoospermia (evidence items include curated and literature sources). This is best viewed as a hypothesis‑generating aggregation of evidence rather than mechanistic proof on its own. (OpenTargets Search: -LIPE)
A 2023 Nature Communications study (publication month December 2023, URL https://doi.org/10.1038/s41467-023-43606-3) describing the peripherally restricted MAGL inhibitor LEI‑515 reports that chemical proteomics identified HSL (LIPE) as the main off‑target in multiple tissues and that this was confirmed by gel‑based activity‑based protein profiling using recombinant human/mouse HSL in HEK293T membranes. The paper therefore cautions that HSL inhibition should be considered when interpreting biological effects attributed solely to MAGL blockade. (jiang2023amonoacylglycerollipase pages 5-6, jiang2023amonoacylglycerollipase pages 10-11)
Quantitatively, the paper reports MAGL IC50 = 25 nM (mouse brain proteome) and large selectivity margins over several other hydrolases/receptors (e.g., >500‑fold over DAGL‑α and ABHD6/12), but the excerpted text does not provide a numeric IC50 for HSL specifically—only identifying it as the main off‑target by ABPP/proteomics. (jiang2023amonoacylglycerollipase pages 5-6)
The same 2023 study notes that although LEI‑515 has HSL off‑target activity, phenotypes in their tested disease models were recapitulated by other MAGL inhibitors and MAGL knockout, leading the authors to conclude that HSL plays a limited role, if any, in those specific pathophysiological contexts; nonetheless, they explicitly state that LEI‑515’s HSL inhibitory activity should be considered, particularly in peripheral tissues where HSL can contribute to MAG pools. (jiang2023amonoacylglycerollipase pages 9-10)
The 2025 Nature Communications structural paper provides a major mechanistic advance by defining physical determinants of LD association (H‑motif; N‑terminal 4‑helix bundle) and reporting phosphorylation‑independent LD binding in their system—shifting the field from a purely phosphorylation‑centric view to a combined model in which intrinsic binding motifs and phosphorylation‑dependent signaling cooperate to regulate LD engagement and lipolysis. (peng2025moleculardeterminantsfor pages 1-2)
Human adipocyte LD proteomics (2023) and high‑quality metabolic disease reviews (2023–2024) increasingly emphasize direct human LD biology and human genetics (FPLD6) as anchors for causal inference, complementing mouse‑dominant mechanistic frameworks. (yang2023regulationoflipolysis pages 1-2, zadoorian2023lipiddropletbiogenesis pages 6-7, harake2024involvementofa pages 12-13)
The following table consolidates verified identity, biochemical function, regulation, localization, genetic disease links, and pharmacology considerations for LIPE/HSL (Q05469).
| Aspect | Current understanding | Recent 2023-2025 evidence | Key citations |
|---|---|---|---|
| Identity | LIPE encodes human hormone-sensitive lipase (HSL), a neutral serine hydrolase in the GDXG lipase family that acts in intracellular neutral-lipid mobilization. Recent primary literature explicitly maps human HSL to UniProt Q05469, with the adipocyte isoform designated Q05469-2. | A 2025 cryo-EM/biochemistry study explicitly states that the analyzed human HSL is UniProt Q05469-2 and confirms its role in canonical lipolysis as the diacylglycerol (DAG) lipase step. Human adipocyte studies and 2024 reviews consistently treat LIPE/HSL as a core lipid-droplet lipase. | (peng2025moleculardeterminantsfor pages 1-2, yang2023regulationoflipolysis pages 1-2) |
| Enzymatic reaction | In the canonical adipocyte lipolysis cascade, ATGL first hydrolyzes TAG to DAG, HSL preferentially hydrolyzes DAG to MAG, and MAG is then hydrolyzed by MAGL to glycerol plus fatty acid. HSL is therefore the principal DAG lipase in regulated lipolysis, although it also hydrolyzes other neutral esters. | Recent reviews and primary studies continue to place HSL centrally in DAG hydrolysis during hormonally stimulated lipolysis. The 2025 structural paper reiterates this step and experimentally validates catalytic activity in recombinant human HSL. | (peng2025moleculardeterminantsfor pages 1-2, harake2024involvementofa pages 10-12, poursharifi2025glycerolipidcyclingin pages 16-18, yang2023regulationoflipolysis pages 1-2) |
| Substrates/specificity | HSL has broad substrate specificity, acting on DAG, TAG, MAG, cholesteryl esters, and retinyl esters, but it strongly prefers DAG over TAG. This broad specificity explains its roles in adipocyte lipolysis, steroidogenic cholesterol mobilization, and retinoid homeostasis. | A 2024 adipocyte study identifies HSL as the major retinyl ester hydrolase in adipose tissue during fasting. A 2023 review summarizes that human HSL hydrolyzes multiple lipid esters with DAG activity markedly exceeding TAG activity. | (nagaroor2023anoverviewof pages 7-10, nagaroor2023anoverviewof pages 4-7, steinhoff2024adipocytehslis pages 1-2) |
| Catalytic residues | Human HSL contains the classical serine-hydrolase catalytic triad Ser424-Asp693-His723 and the conserved GXSXG motif. Catalysis depends on the active-site serine, consistent with inhibition by generic serine-reactive inhibitors. | The 2025 cryo-EM/biochemistry study reports that S424A abolishes activity, directly validating Ser424 as essential. The 2023 review independently summarizes Ser424, Asp693, and His723 as the catalytic triad in human HSL. | (peng2025moleculardeterminantsfor pages 1-2, nagaroor2023anoverviewof pages 7-10) |
| Structure/domains | HSL comprises an N-terminal regulatory/lipid-binding region and a C-terminal catalytic α/β-hydrolase region. Domain architecture includes an N-terminal 4-helix bundle and a regulatory region that contains phosphorylation and lipid-droplet interaction determinants. | A 2025 cryo-EM structure of human HSL at 3.4 Å resolved its homodimeric architecture and identified lipid-droplet binding determinants. Figure evidence in that paper maps the domain architecture and key motifs. | (peng2025moleculardeterminantsfor pages 1-2, peng2025moleculardeterminantsfor media 06b3eac4, peng2025moleculardeterminantsfor media 9c4ad302) |
| Lipid droplet localization | HSL is largely cytosolic basally and relocates to the lipid-droplet (LD) surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated droplets. LD recruitment is a major regulatory step controlling substrate access. | Human adipocyte proximity-labeling identified LIPE among PLIN1-interacting LD proteins in 2023. The 2025 structure/mechanism paper identified two intrinsic LD-binding elements: residues 489-538 (the “H-motif”) and the N-terminal 4-helix bundle; LD binding in that system was phosphorylation-independent. | (yang2023regulationoflipolysis pages 1-1, yang2023regulationoflipolysis pages 1-2, peng2025moleculardeterminantsfor pages 1-2, peng2025moleculardeterminantsfor media 06b3eac4) |
| Regulation/signaling | Classical activation occurs through β-adrenergic/Gs/cAMP/PKA signaling, with PKA phosphorylation of HSL and PLIN1 promoting lipolysis and HSL access to LDs; insulin antagonizes this program. PLIN1 phosphorylation is a key gatekeeper for HSL recruitment to droplets. | Recent human adipocyte work confirms cAMP-regulated LD lipolysis machinery, while a 2025 study refines the model by showing that intrinsic LD binding can occur independently of PKA phosphorylation. Additional 2024 work shows alternative lipolytic control pathways, such as oxytocin/ERK signaling, can enhance glycerol release without engaging canonical PKA in the same way. | (harake2024involvementofa pages 10-12, yang2023regulationoflipolysis pages 1-2, peng2025moleculardeterminantsfor pages 1-2, li2024controloflipolysis pages 1-5) |
| Physiological roles | LIPE/HSL mobilizes fatty acids from adipocyte lipid droplets for systemic energy supply, contributes to cholesteryl ester hydrolysis in steroidogenic tissues, and participates in retinoid mobilization. It also influences adipocyte differentiation/signaling through ligand generation that may affect PPARγ activity. | In 2024, adipocyte HSL was shown to be required for maintenance of circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A role. Recent disease-focused reviews also link LIPE deficiency to impaired endogenous PPARγ ligand generation and adipose dysfunction. | (steinhoff2024adipocytehslis pages 1-2, zadoorian2023lipiddropletbiogenesis pages 6-7) |
| Disease genetics | Biallelic loss-of-function LIPE variants cause familial partial lipodystrophy type 6 / LIPE-related familial partial lipodystrophy, with abnormal fat distribution and severe metabolic complications. Reported manifestations include diabetes, hypertriglyceridemia, hepatic steatosis, myopathy, and sometimes retinal, renal, or neurologic findings. | A 2024 case report described the first Chinese FPLD6 patient with compound heterozygous pathogenic frameshifts (p.Glu833LysfsTer22 and p.Ser902ThrfsTer27) and a phenotype including diabetes, hypertriglyceridemia, fatty liver, retinal changes, neuropathy, and renal tubular injury. Open Targets also lists LIPE associations with LIPE-related familial partial lipodystrophy and azoospermia. | (zhou2024casereportfirst pages 3-5, zhou2024casereportfirst pages 1-2, harake2024involvementofa pages 10-12, OpenTargets Search: -LIPE) |
| Pharmacology/off-target | HSL can be inhibited by generic serine-reactive inhibitors, but selective clinical pharmacology for HSL itself remains limited. A practical issue in lipid-hydrolase drug discovery is that HSL may appear as an off-target when compounds are developed against nearby serine hydrolases. | In a 2023 Nature Communications MAGL inhibitor study, LEI-515 was profiled as a potent MAGL inhibitor but HSL/LIPE emerged as the main off-target by chemical proteomics and ABPP. The authors caution that HSL inhibition should be considered when interpreting peripheral MAGL biology, even though comparison with MAGL knockout and other MAGL inhibitors suggested limited HSL contribution in their tested disease models. | (jiang2023amonoacylglycerollipase pages 5-6, jiang2023amonoacylglycerollipase pages 10-11, jiang2023amonoacylglycerollipase pages 9-10, jiang2023amonoacylglycerollipase pages 6-6) |
| Key quantitative data | Quantitative biochemical and physiological values support LIPE function. Recombinant human HSL showed p-nitrophenyl butyrate hydrolysis with Km = 186.1 µM and kcat = 124.5 s^-1, and DAG hydrolysis has been reported as substantially greater than TAG hydrolysis. | LEI-515 inhibited MAGL in mouse brain proteome with IC50 = 25 nM and showed reported selectivity of >500-fold over DAGL-α and ABHD6/12 and >100-fold over a broader enzyme/receptor panel, although no numeric HSL IC50 was given in the cited excerpt. In physiology, oxytocin increased glycerol release from adipocytes by ~1.6-fold, and HSL-null mouse models cited in recent reviews showed ~2.5-fold higher LD-TAG and ~30% lower basal plasma NEFAs. | (peng2025moleculardeterminantsfor pages 1-2, nagaroor2023anoverviewof pages 7-10, li2024controloflipolysis pages 1-5, jiang2023amonoacylglycerollipase pages 5-6, harake2024involvementofa pages 12-13) |
Table: This table summarizes verified identity, biochemistry, regulation, localization, disease relevance, and pharmacology for human LIPE/HSL (UniProt Q05469). It emphasizes recent 2023-2025 evidence and includes quantitative values where available.
References
(peng2025moleculardeterminantsfor pages 1-2): Han Peng, Qikui Xu, Ting Zhang, Jiakai Zhu, Jinheng Pan, Xiaoyu Guan, Shan Feng, Jianping Wu, and Qiuyu Hu. Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets. Nature Communications, Apr 2025. URL: https://doi.org/10.1038/s41467-025-58887-z, doi:10.1038/s41467-025-58887-z. This article has 10 citations and is from a highest quality peer-reviewed journal.
(nagaroor2023anoverviewof pages 4-7): Vijayalakshmi Nagaroor and Sathyanarayana N. Gummadi. An overview of mammalian and microbial hormone-sensitive lipases (lipolytic family iv): biochemical properties and industrial applications. Biotechnology and Genetic Engineering Reviews, 39:281-310, Sep 2023. URL: https://doi.org/10.1080/02648725.2022.2127071, doi:10.1080/02648725.2022.2127071. This article has 9 citations and is from a peer-reviewed journal.
(yang2023regulationoflipolysis pages 1-2): Qin Yang, Zinger Yang Loureiro, Anand Desai, Tiffany DeSouza, Kaida Li, Hui Wang, Sarah M Nicoloro, Javier Solivan-Rivera, and Silvia Corvera. Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets. PNAS Nexus, May 2023. URL: https://doi.org/10.1093/pnasnexus/pgad420, doi:10.1093/pnasnexus/pgad420. This article has 13 citations and is from a peer-reviewed journal.
(harake2024involvementofa pages 10-12): Sami N. Al Harake, Yasamin Abedin, Fatema Hatoum, Nour Zahraa Nassar, Ali Ali, Aline Nassar, Amjad Kanaan, Samer Bazzi, Sami Azar, Frederic Harb, and Hilda E. Ghadieh. Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities. Adipocyte, Sep 2024. URL: https://doi.org/10.1080/21623945.2024.2403380, doi:10.1080/21623945.2024.2403380. This article has 2 citations.
(poursharifi2025glycerolipidcyclingin pages 16-18): Pegah Poursharifi, S. R. Murthy Madiraju, Abel Oppong, Shingo Kajimura, Christopher J. Nolan, Denis P. Blondin, and Marc Prentki. Glycerolipid cycling in thermogenesis, energy homeostasis, signaling, and diseases. Physiological Reviews, 105:2449-2499, Oct 2025. URL: https://doi.org/10.1152/physrev.00024.2024, doi:10.1152/physrev.00024.2024. This article has 13 citations and is from a highest quality peer-reviewed journal.
(nagaroor2023anoverviewof pages 7-10): Vijayalakshmi Nagaroor and Sathyanarayana N. Gummadi. An overview of mammalian and microbial hormone-sensitive lipases (lipolytic family iv): biochemical properties and industrial applications. Biotechnology and Genetic Engineering Reviews, 39:281-310, Sep 2023. URL: https://doi.org/10.1080/02648725.2022.2127071, doi:10.1080/02648725.2022.2127071. This article has 9 citations and is from a peer-reviewed journal.
(peng2025moleculardeterminantsfor media 06b3eac4): Han Peng, Qikui Xu, Ting Zhang, Jiakai Zhu, Jinheng Pan, Xiaoyu Guan, Shan Feng, Jianping Wu, and Qiuyu Hu. Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets. Nature Communications, Apr 2025. URL: https://doi.org/10.1038/s41467-025-58887-z, doi:10.1038/s41467-025-58887-z. This article has 10 citations and is from a highest quality peer-reviewed journal.
(peng2025moleculardeterminantsfor media 5041a669): Han Peng, Qikui Xu, Ting Zhang, Jiakai Zhu, Jinheng Pan, Xiaoyu Guan, Shan Feng, Jianping Wu, and Qiuyu Hu. Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets. Nature Communications, Apr 2025. URL: https://doi.org/10.1038/s41467-025-58887-z, doi:10.1038/s41467-025-58887-z. This article has 10 citations and is from a highest quality peer-reviewed journal.
(yang2023regulationoflipolysis pages 1-1): Qin Yang, Zinger Yang Loureiro, Anand Desai, Tiffany DeSouza, Kaida Li, Hui Wang, Sarah M Nicoloro, Javier Solivan-Rivera, and Silvia Corvera. Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets. PNAS Nexus, May 2023. URL: https://doi.org/10.1093/pnasnexus/pgad420, doi:10.1093/pnasnexus/pgad420. This article has 13 citations and is from a peer-reviewed journal.
(li2024controloflipolysis pages 1-5): Erwei Li, Luhong Wang, Daqing Wang, Jingyi Chi, Gordon I. Smith, Samuel Klein, Paul Cohen, and Evan D. Rosen. Control of lipolysis by a population of oxytocinergic sympathetic neurons. Nature, 625:175-180, Sep 2024. URL: https://doi.org/10.1101/2022.09.27.509745, doi:10.1101/2022.09.27.509745. This article has 45 citations and is from a highest quality peer-reviewed journal.
(steinhoff2024adipocytehslis pages 1-2): Julia S. Steinhoff, Carina Wagner, Henriette E. Dähnhardt, Kristina Košić, Yueming Meng, U. Taschler, Laura Pajed, Na Yang, Sascha Wulff, Marie F. Kiefer, Konstantin M. Petricek, Roberto E Flores, Chen Li, Sarah Dittrich, Manuela Sommerfeld, Hervé Guillou, Andrea Henze, Jens Raila, Sylvia J Wowro, Gabriele Schoiswohl, A. Lass, and M. Schupp. Adipocyte hsl is required for maintaining circulating vitamin a and rbp4 levels during fasting. EMBO Reports, 25:2878-2895, May 2024. URL: https://doi.org/10.1038/s44319-024-00158-x, doi:10.1038/s44319-024-00158-x. This article has 16 citations and is from a highest quality peer-reviewed journal.
(zhou2024casereportfirst pages 1-2): Yimeng Zhou, Lin Zhang, Yang Ding, and Yongzhen Zhai. Case report: first chinese patient with family partial lipodystrophy type 6 due to novel compound heterozygous mutations in the lipe gene. Frontiers in Genetics, Jul 2024. URL: https://doi.org/10.3389/fgene.2024.1417613, doi:10.3389/fgene.2024.1417613. This article has 5 citations and is from a peer-reviewed journal.
(zhou2024casereportfirst pages 3-5): Yimeng Zhou, Lin Zhang, Yang Ding, and Yongzhen Zhai. Case report: first chinese patient with family partial lipodystrophy type 6 due to novel compound heterozygous mutations in the lipe gene. Frontiers in Genetics, Jul 2024. URL: https://doi.org/10.3389/fgene.2024.1417613, doi:10.3389/fgene.2024.1417613. This article has 5 citations and is from a peer-reviewed journal.
(harake2024involvementofa pages 12-13): Sami N. Al Harake, Yasamin Abedin, Fatema Hatoum, Nour Zahraa Nassar, Ali Ali, Aline Nassar, Amjad Kanaan, Samer Bazzi, Sami Azar, Frederic Harb, and Hilda E. Ghadieh. Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities. Adipocyte, Sep 2024. URL: https://doi.org/10.1080/21623945.2024.2403380, doi:10.1080/21623945.2024.2403380. This article has 2 citations.
(OpenTargets Search: -LIPE): Open Targets Query (-LIPE, 29 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(jiang2023amonoacylglycerollipase pages 5-6): Ming Jiang, Mirjam C. W. Huizenga, Jonah L. Wirt, Janos Paloczi, Avand Amedi, Richard J. B. H. N. van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F. Driever, Bogdan I. Florea, Uwe Grether, Antonius P. A. Janssen, Thomas Hankemeier, Laura H. Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F. Stevens, Daan van der Vliet, Tom van der Wel, Matthias B. Wittwer, Constant A. A. van Boeckel, Pal Pacher, Andrea G. Hohmann, and Mario van der Stelt. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43606-3, doi:10.1038/s41467-023-43606-3. This article has 62 citations and is from a highest quality peer-reviewed journal.
(jiang2023amonoacylglycerollipase pages 10-11): Ming Jiang, Mirjam C. W. Huizenga, Jonah L. Wirt, Janos Paloczi, Avand Amedi, Richard J. B. H. N. van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F. Driever, Bogdan I. Florea, Uwe Grether, Antonius P. A. Janssen, Thomas Hankemeier, Laura H. Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F. Stevens, Daan van der Vliet, Tom van der Wel, Matthias B. Wittwer, Constant A. A. van Boeckel, Pal Pacher, Andrea G. Hohmann, and Mario van der Stelt. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43606-3, doi:10.1038/s41467-023-43606-3. This article has 62 citations and is from a highest quality peer-reviewed journal.
(jiang2023amonoacylglycerollipase pages 9-10): Ming Jiang, Mirjam C. W. Huizenga, Jonah L. Wirt, Janos Paloczi, Avand Amedi, Richard J. B. H. N. van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F. Driever, Bogdan I. Florea, Uwe Grether, Antonius P. A. Janssen, Thomas Hankemeier, Laura H. Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F. Stevens, Daan van der Vliet, Tom van der Wel, Matthias B. Wittwer, Constant A. A. van Boeckel, Pal Pacher, Andrea G. Hohmann, and Mario van der Stelt. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43606-3, doi:10.1038/s41467-023-43606-3. This article has 62 citations and is from a highest quality peer-reviewed journal.
(zadoorian2023lipiddropletbiogenesis pages 6-7): Armella Zadoorian, Ximing Du, and Hongyuan Yang. Lipid droplet biogenesis and functions in health and disease. Nature Reviews. Endocrinology, 19:1-17, May 2023. URL: https://doi.org/10.1038/s41574-023-00845-0, doi:10.1038/s41574-023-00845-0. This article has 626 citations.
(peng2025moleculardeterminantsfor media 9c4ad302): Han Peng, Qikui Xu, Ting Zhang, Jiakai Zhu, Jinheng Pan, Xiaoyu Guan, Shan Feng, Jianping Wu, and Qiuyu Hu. Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets. Nature Communications, Apr 2025. URL: https://doi.org/10.1038/s41467-025-58887-z, doi:10.1038/s41467-025-58887-z. This article has 10 citations and is from a highest quality peer-reviewed journal.
(jiang2023amonoacylglycerollipase pages 6-6): Ming Jiang, Mirjam C. W. Huizenga, Jonah L. Wirt, Janos Paloczi, Avand Amedi, Richard J. B. H. N. van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F. Driever, Bogdan I. Florea, Uwe Grether, Antonius P. A. Janssen, Thomas Hankemeier, Laura H. Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F. Stevens, Daan van der Vliet, Tom van der Wel, Matthias B. Wittwer, Constant A. A. van Boeckel, Pal Pacher, Andrea G. Hohmann, and Mario van der Stelt. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43606-3, doi:10.1038/s41467-023-43606-3. This article has 62 citations and is from a highest quality peer-reviewed journal.
id: Q05469
gene_symbol: LIPE
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'LIPE encodes hormone-sensitive lipase (HSL), an intracellular neutral-lipid serine hydrolase
that is recruited from the cytosol to lipid droplets during stimulated lipolysis. Its best-supported
core catalytic role is hydrolysis of diacylglycerol to monoacylglycerol and fatty acid in the adipocyte
lipolysis cascade; it also hydrolyzes other neutral esters, including triacylglycerols, cholesteryl
esters, monoacylglycerols, and retinyl esters in tissue-specific contexts.'
existing_annotations:
- term:
id: GO:0004771
label: sterol ester esterase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate
activity rather than the central adipocyte DAG-lipase role.
action: KEEP_AS_NON_CORE
reason: sterol ester esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: PMID:15716583
supporting_text: Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis
of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for
adrenal steroidogenesis.
- term:
id: GO:0004806
label: triacylglycerol lipase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned
primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
action: KEEP_AS_NON_CORE
reason: triacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0005829
label: cytosol
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: The cytosol annotation is consistent with basal HSL localization before stimulated
lipid-droplet recruitment.
action: ACCEPT
reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0019433
label: triglyceride catabolic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: HSL acts within the canonical triglyceride catabolic cascade by hydrolyzing DAG
produced from TAG.
action: ACCEPT
reason: triglyceride catabolic process is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0042572
label: retinol metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Retinol metabolism is supported by recent physiology but is a tissue/context-specific
secondary role rather than the primary neutral-lipid lipolysis function.
action: KEEP_AS_NON_CORE
reason: retinol metabolic process is supported, but it is secondary to the core DAG-lipase
role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In 2024, adipocyte HSL was shown to be required for maintenance of
circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A
role.
- term:
id: GO:0004771
label: sterol ester esterase activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate
activity rather than the central adipocyte DAG-lipase role.
action: KEEP_AS_NON_CORE
reason: sterol ester esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: PMID:15716583
supporting_text: Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis
of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for
adrenal steroidogenesis.
- term:
id: GO:0004806
label: triacylglycerol lipase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned
primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
action: KEEP_AS_NON_CORE
reason: triacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0005811
label: lipid droplet
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: The lipid droplet annotation captures the regulated site where HSL gains access to
stored neutral lipid substrates.
action: ACCEPT
reason: lipid droplet is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: The cytosol annotation is consistent with basal HSL localization before stimulated
lipid-droplet recruitment.
action: ACCEPT
reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Plasma membrane association has experimental support through PTRF/caveola studies,
but it is not the main functional location of HSL.
action: KEEP_AS_NON_CORE
reason: plasma membrane is supported, but it is secondary to the core DAG-lipase role.
supported_by:
- reference_id: PMID:17026959
supporting_text: In the plasma membrane PTRF was specifically bound to a
triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase
(HSL).
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0005901
label: caveola
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Caveola association is supported in adipocytes through PTRF, but it is secondary to
cytosol-to-lipid-droplet recruitment during lipolysis.
action: KEEP_AS_NON_CORE
reason: caveola is supported, but it is secondary to the core DAG-lipase role.
supported_by:
- reference_id: PMID:17026959
supporting_text: In the plasma membrane PTRF was specifically bound to a
triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase
(HSL).
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0006629
label: lipid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The generic lipid metabolic process annotation is directionally correct but too broad
for HSL. Lipid catabolic process, and more specifically diacylglycerol catabolic process,
better capture the reviewed function.
action: MODIFY
reason: lipid metabolic process is less informative than the reviewed LIPE/HSL lipolysis term.
proposed_replacement_terms:
- id: GO:0016042
label: lipid catabolic process
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0008202
label: steroid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Steroid metabolic process is plausible through cholesteryl ester hydrolysis in
steroidogenic tissues but is not the central LIPE function.
action: KEEP_AS_NON_CORE
reason: steroid metabolic process is supported, but it is secondary to the core DAG-lipase
role.
supported_by:
- reference_id: PMID:15716583
supporting_text: Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis
of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for
adrenal steroidogenesis.
- term:
id: GO:0008203
label: cholesterol metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Cholesterol metabolism is supported through cholesteryl ester hydrolysis, but this is
a secondary substrate context.
action: KEEP_AS_NON_CORE
reason: cholesterol metabolic process is supported, but it is secondary to the core DAG-lipase
role.
supported_by:
- reference_id: PMID:15716583
supporting_text: The relatively higher turnover of HSL on CO observed in vitro adds
further molecular insight on the physiological importance of HSL in cholesteryl ester
catabolism in vivo.
- term:
id: GO:0016042
label: lipid catabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Lipid catabolic process is supported because LIPE/HSL hydrolyzes neutral lipid esters
during lipolysis.
action: ACCEPT
reason: lipid catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0016298
label: lipase activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Generic lipase activity should be refined to diacylglycerol lipase activity because
DAG hydrolysis is the best-supported core catalytic step.
action: MODIFY
reason: lipase activity is less informative than the reviewed LIPE/HSL lipolysis term.
proposed_replacement_terms:
- id: GO:0120516
label: diacylglycerol lipase activity
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0016787
label: hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Generic hydrolase activity obscures the specific serine-lipase reaction supported for
LIPE/HSL.
action: MODIFY
reason: hydrolase activity is less informative than the reviewed LIPE/HSL lipolysis term.
proposed_replacement_terms:
- id: GO:0120516
label: diacylglycerol lipase activity
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0047372
label: monoacylglycerol lipase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Monoacylglycerol lipase activity is consistent with broad HSL substrate specificity,
but the dominant physiological lipolysis role is DAG hydrolysis.
action: KEEP_AS_NON_CORE
reason: monoacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0047376
label: all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity
evidence_type: IEA
original_reference_id: GO_REF:0000116
review:
summary: Retinyl-palmitate hydrolase activity is supported as part of retinoid mobilization
but should be treated as a secondary substrate-specific function.
action: KEEP_AS_NON_CORE
reason: all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity is
supported, but it is secondary to the core DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In 2024, adipocyte HSL was shown to be required for maintenance of
circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A
role.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0050253
label: retinyl-palmitate esterase activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Retinyl-palmitate esterase activity is supported as part of retinoid mobilization but
is secondary to the primary DAG lipase role.
action: KEEP_AS_NON_CORE
reason: retinyl-palmitate esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In 2024, adipocyte HSL was shown to be required for maintenance of
circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A
role.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0120516
label: diacylglycerol lipase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
action: ACCEPT
reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Protein binding is too generic for curation of LIPE; the reviewed biology is better
represented by regulated localization to PLIN1-coated lipid droplets and specific lipid
hydrolase activities.
action: MARK_AS_OVER_ANNOTATED
reason: protein binding overstates or obscures the specific supported LIPE function.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: The cytosol annotation is consistent with basal HSL localization before stimulated
lipid-droplet recruitment.
action: ACCEPT
reason: cytosol is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0019433
label: triglyceride catabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000041
review:
summary: HSL acts within the canonical triglyceride catabolic cascade by hydrolyzing DAG
produced from TAG.
action: ACCEPT
reason: triglyceride catabolic process is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0004771
label: sterol ester esterase activity
evidence_type: IDA
original_reference_id: PMID:15716583
review:
summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate
activity rather than the central adipocyte DAG-lipase role.
action: KEEP_AS_NON_CORE
reason: sterol ester esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: PMID:15716583
supporting_text: Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis
of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for
adrenal steroidogenesis.
- term:
id: GO:0004771
label: sterol ester esterase activity
evidence_type: IDA
original_reference_id: PMID:8812477
review:
summary: Sterol ester esterase activity is supported as a secondary neutral-ester substrate
activity rather than the central adipocyte DAG-lipase role.
action: KEEP_AS_NON_CORE
reason: sterol ester esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: PMID:15716583
supporting_text: Hormone-sensitive lipase (HSL) contributes importantly to the hydrolysis
of cholesteryl ester in steroidogenic tissues, releasing the cholesterol required for
adrenal steroidogenesis.
- term:
id: GO:0004806
label: triacylglycerol lipase activity
evidence_type: IDA
original_reference_id: PMID:15716583
review:
summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned
primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
action: KEEP_AS_NON_CORE
reason: triacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0004806
label: triacylglycerol lipase activity
evidence_type: IDA
original_reference_id: PMID:15955102
review:
summary: Triacylglycerol lipase activity is biochemically supported, but HSL is positioned
primarily as the DAG lipase downstream of ATGL in stimulated lipolysis.
action: KEEP_AS_NON_CORE
reason: triacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0016020
label: membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Generic membrane association is retained as non-core because HSL can associate with
caveolae and lipid droplets while remaining primarily a regulated soluble lipase.
action: KEEP_AS_NON_CORE
reason: membrane is supported, but it is secondary to the core DAG-lipase role.
supported_by:
- reference_id: PMID:17026959
supporting_text: In the plasma membrane PTRF was specifically bound to a
triacylglycerol-metabolizing subclass of caveolae containing hormone-sensitive lipase
(HSL).
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0046340
label: diacylglycerol catabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Diacylglycerol catabolic process is the most precise biological-process annotation
for HSL in the lipolysis cascade.
action: ACCEPT
reason: diacylglycerol catabolic process is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- term:
id: GO:0046485
label: ether lipid metabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Ether lipid metabolic process is not supported by the reviewed LIPE literature; the
evidence supports neutral acylglycerol, sterol ester, and retinyl ester hydrolysis instead.
action: MARK_AS_OVER_ANNOTATED
reason: ether lipid metabolic process overstates or obscures the specific supported LIPE
function.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0047372
label: monoacylglycerol lipase activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Monoacylglycerol lipase activity is consistent with broad HSL substrate specificity,
but the dominant physiological lipolysis role is DAG hydrolysis.
action: KEEP_AS_NON_CORE
reason: monoacylglycerol lipase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0050253
label: retinyl-palmitate esterase activity
evidence_type: IDA
original_reference_id: PMID:15955102
review:
summary: Retinyl-palmitate esterase activity is supported as part of retinoid mobilization but
is secondary to the primary DAG lipase role.
action: KEEP_AS_NON_CORE
reason: retinyl-palmitate esterase activity is supported, but it is secondary to the core
DAG-lipase role.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In 2024, adipocyte HSL was shown to be required for maintenance of
circulating retinol and RBP4 during fasting, establishing a concrete systemic vitamin A
role.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0120516
label: diacylglycerol lipase activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
action: ACCEPT
reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0120516
label: diacylglycerol lipase activity
evidence_type: IDA
original_reference_id: PMID:19800417
review:
summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
action: ACCEPT
reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0120516
label: diacylglycerol lipase activity
evidence_type: IDA
original_reference_id: PMID:8812477
review:
summary: Diacylglycerol lipase activity is the best-supported core molecular function of HSL.
action: ACCEPT
reason: diacylglycerol lipase activity is supported as part of LIPE/HSL core lipid-droplet
lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0005811
label: lipid droplet
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: The lipid droplet annotation captures the regulated site where HSL gains access to
stored neutral lipid substrates.
action: ACCEPT
reason: lipid droplet is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0016042
label: lipid catabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Lipid catabolic process is supported because LIPE/HSL hydrolyzes neutral lipid esters
during lipolysis.
action: ACCEPT
reason: lipid catabolic process is supported as part of LIPE/HSL core lipid-droplet lipolysis.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple
sources emphasize that activity toward **DAG is markedly higher than toward TAG**,
positioning HSL as the dominant DAG lipase in stimulated lipolysis rather than the
initiating TAG lipase.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17026959
review:
summary: Protein binding is too generic for curation of LIPE; the reviewed biology is better
represented by regulated localization to PLIN1-coated lipid droplets and specific lipid
hydrolase activities.
action: MARK_AS_OVER_ANNOTATED
reason: protein binding overstates or obscures the specific supported LIPE function.
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- term:
id: GO:0006468
label: protein phosphorylation
evidence_type: TAS
original_reference_id: PMID:3420405
review:
summary: This annotation treats LIPE as if it performs protein phosphorylation. The cited
biology describes HSL as a phosphorylation-regulated lipase, not a kinase.
action: REMOVE
reason: LIPE is regulated by phosphorylation but does not catalyze protein phosphorylation.
supported_by:
- reference_id: PMID:3420405
supporting_text: Hormone-sensitive lipase, a key enzyme in fatty acid mobilization,
overall energy homeostasis, and possibly steroidogenesis, is acutely controlled through
reversible phosphorylation by catecholamines and insulin.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000041
title: Gene Ontology annotation based on UniPathway vocabulary mapping
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
mapping, accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000116
title: Automatic Gene Ontology annotation based on Rhea mapping
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:15716583
title: Continuous monitoring of cholesterol oleate hydrolysis by hormone-sensitive lipase and
other cholesterol esterases.
findings: []
- id: PMID:15955102
title: Identification of a novel keratinocyte retinyl ester hydrolase as a transacylase and
lipase.
findings: []
- id: PMID:17026959
title: Association and insulin regulated translocation of hormone-sensitive lipase with PTRF.
findings: []
- id: PMID:19800417
title: In vitro stereoselective hydrolysis of diacylglycerols by hormone-sensitive lipase.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:3420405
title: 'Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3.'
findings: []
- id: PMID:8812477
title: Molecular cloning, genomic organization, and expression of a testicular isoform of
hormone-sensitive lipase.
findings: []
- id: file:human/LIPE/LIPE-deep-research-falcon.md
title: Falcon deep research synthesis for LIPE
findings: []
core_functions:
- description: Cytosol-to-lipid-droplet diacylglycerol lipase activity during hormonally
stimulated neutral-lipid mobilization.
molecular_function:
id: GO:0120516
label: diacylglycerol lipase activity
directly_involved_in:
- id: GO:0046340
label: diacylglycerol catabolic process
- id: GO:0019433
label: triglyceride catabolic process
- id: GO:0016042
label: lipid catabolic process
locations:
- id: GO:0005829
label: cytosol
- id: GO:0005811
label: lipid droplet
supported_by:
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: In the canonical LD lipolysis cascade, **ATGL (PNPLA2)** initiates
triacylglycerol (TAG) breakdown to diacylglycerol (DAG), **HSL (LIPE)** then
preferentially hydrolyzes **DAG→monoacylglycerol (MAG) + free fatty acid**, and MAG is
further hydrolyzed by **MAGL** to glycerol and fatty acids.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL is largely cytosolic basally and relocates to the lipid-droplet (LD)
surface during stimulated lipolysis, where it interacts functionally with PLIN1-coated
droplets. LD recruitment is a major regulatory step controlling substrate access.
- reference_id: file:human/LIPE/LIPE-deep-research-falcon.md
supporting_text: HSL has **broad substrate specificity**, with reported activity against
**TAG, DAG, MAG, cholesteryl esters, retinyl esters**, and other esters; multiple sources
emphasize that activity toward **DAG is markedly higher than toward TAG**, positioning HSL
as the dominant DAG lipase in stimulated lipolysis rather than the initiating TAG lipase.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []