Intracellular triacylglycerol lipolysis (ABHD5-ATGL, HSL, MGLL)

Neutral (cytoplasmic) lipolysis is the stepwise hydrolysis of triacylglycerol stored in cytoplasmic lipid droplets to glycerol and three fatty acids. Adipose triglyceride lipase (ATGL/PNPLA2) catalyzes the first, rate-limiting step, hydrolyzing triacylglycerol to diacylglycerol on the lipid droplet surface; its activity is strongly stimulated by the non-catalytic co-activator ABHD5 (CGI-58). Hormone-sensitive lipase (HSL/LIPE) then hydrolyzes diacylglycerol to monoacylglycerol, and monoglyceride lipase (MGLL) completes the pathway by hydrolyzing monoacylglycerol to glycerol and a fatty acid. The pathway operates in adipocytes, where it supplies fatty acids to other tissues during fasting, and in most other cells including skeletal and cardiac muscle. Biallelic loss of ABHD5 causes neutral lipid storage disease with ichthyosis (Chanarin-Dorfman syndrome) and biallelic loss of PNPLA2 causes neutral lipid storage disease with myopathy; both show triacylglycerol accumulation in cytoplasmic droplets of many tissues.

MODULE:triacylglycerol_lipolysisDRAFTMetabolic Pathwaymodules/triacylglycerol_lipolysis.yaml
triglyceride catabolic processGO:0019433
GO:0019433
triglyceride catabolic process
The module is grounded in triglyceride catabolic process (GO:0019433), the hydrolysis of triacylglycerol to glycerol and fatty acids.
file:human/PNPLA2/PNPLA2-ai-review.yaml
PNPLA2 gene review (human)
The ATGL step (UniProtKB:Q96AD5, GO:0004806 triacylglycerol lipase activity on lipid droplets) matches the completed human PNPLA2 review.
file:human/ABHD5/ABHD5-ai-review.yaml
ABHD5 gene review (human)
The ABHD5 co-activator step (UniProtKB:Q8WTS1, GO:0060229 lipase activator activity) matches the completed human ABHD5 review, which removes the contested intrinsic acyltransferase and hydrolase activities.
file:human/LIPE/LIPE-ai-review.yaml
LIPE gene review (human)
The HSL diacylglycerol lipase step (UniProtKB:Q05469, GO:0120516) matches the completed human LIPE review.
PMID:16679289
Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome.
CGI-58/ABHD5 binds ATGL and stimulates its triacylglycerol hydrolase activity.
CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold.
5Nodes
4Parts
0Variant Sets
0Variants
4Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:triacylglycerol_lipolysis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (8 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
abhd5_activator ABHD5 (human)
UniProtKB:Q8WTS1
Family Representative 		lipase activator activity
GO:0060229 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atgl_activity PNPLA2 / ATGL (human)
UniProtKB:Q96AD5
Family Representative 		triacylglycerol lipase activity
GO:0004806 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsl_activity LIPE / HSL (human)
UniProtKB:Q05469
Family Representative 		diacylglycerol lipase activity
GO:0120516 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mgll_activity MGLL (human)
UniProtKB:Q99685
Family Representative 		monoacylglycerol lipase activity
GO:0047372 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
abhd5_activator ABHD5 subfamily of alpha/beta-hydrolase-fold proteins
PANTHER:PTHR42886:SF34
Family 		lipase activator activity
GO:0060229 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR42886:SF34.
atgl_activity PNPLA2 subfamily of patatin-domain lipases
PANTHER:PTHR12406:SF29
Family 		triacylglycerol lipase activity
GO:0004806 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12406:SF29.
hsl_activity hormone-sensitive lipase subfamily
PANTHER:PTHR23025:SF3
Family 		diacylglycerol lipase activity
GO:0120516 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23025:SF3.
mgll_activity monoglyceride lipase (MGLL)
Family 		monoacylglycerol lipase activity
GO:0047372 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (3/4 grounded genes reviewed)

3 complete review(s) · 2 with deep research · 1 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
ABHD5 Q8WTS1 ✓ ✓ ✗
LIPE Q05469 ✓ ✓ ✓
PNPLA2 Q96AD5 ✓ ✓ ✓
MGLL (human) Q99685 ✗ — —

Details

Context
lipid dropletGO:0005811 cytosolGO:0005829
Intracellular triacylglycerol lipolysisMetabolic Pathwaytriacylglycerol_lipolysis
triglyceride catabolic processGO:0019433
Context
lipid dropletGO:0005811 cytosolGO:0005829

Intracellular (neutral) triacylglycerol lipolysis, grounded to the completed human PNPLA2, ABHD5 and LIPE gene reviews. MGLL has no gene review yet, so its PANTHER family id is left unasserted and its step is grounded to the Reactome acyl-chain remodeling summary. Inhibitory regulators (G0S2, perilipins, PLIN5 sequestration of ABHD5) and hormonal control of HSL by PKA phosphorylation are not yet modelled. Lysosomal acid lipolysis (LIPA, lysosomal lumen) is a separate pathway acting on endocytosed and autophagocytosed lipid and is not part of this module.

Connections

tgl_abhd5_coactivation -> tgl_atgl Positively Regulates
ABHD5 binds ATGL and stimulates its triacylglycerol hydrolase activity on the lipid droplet.
tgl_atgl -> tgl_hsl Provides Input For
ATGL produces the diacylglycerol that HSL hydrolyzes.
tgl_hsl -> tgl_mgll Provides Input For
HSL produces the monoacylglycerol that MGLL hydrolyzes.
Part 1: co-activation of the rate-limiting lipase
ABHD5 (CGI-58) co-activation of ATGLRegulatory Steptgl_abhd5_coactivation

Annotons

ABHD5: ATGL co-activator
abhd5_activator
Participant: Family: ABHD5 subfamily of alpha/beta-hydrolase-fold proteins
Family:
ABHD5 subfamily of alpha/beta-hydrolase-fold proteinsPANTHER:PTHR42886:SF34
Representative Members: ABHD5 (human)UniProtKB:Q8WTS1

Function

lipase activator activityGO:0060229

Locations

lipid dropletGO:0005811

Binds ATGL on the lipid droplet and stimulates its triacylglycerol hydrolase activity.

Part 2: rate-limiting triacylglycerol hydrolysis
ATGL (PNPLA2) triacylglycerol hydrolysisReactiontgl_atgl

Annotons

PNPLA2/ATGL: adipose triglyceride lipase
atgl_activity
Participant: Family: PNPLA2 subfamily of patatin-domain lipases
Family:
PNPLA2 subfamily of patatin-domain lipasesPANTHER:PTHR12406:SF29
Representative Members: PNPLA2 / ATGL (human)UniProtKB:Q96AD5

Function

triacylglycerol lipase activityGO:0004806
Substrates: triacylglycerol H2O
Products: diacylglycerol fatty acid

Locations

lipid dropletGO:0005811

Hydrolyzes stored triacylglycerol to diacylglycerol and a fatty acid.

Part 3: diacylglycerol hydrolysis
HSL (LIPE) diacylglycerol hydrolysisReactiontgl_hsl

Annotons

LIPE/HSL: hormone-sensitive lipase
hsl_activity
Participant: Family: hormone-sensitive lipase subfamily
Family:
hormone-sensitive lipase subfamilyPANTHER:PTHR23025:SF3
Representative Members: LIPE / HSL (human)UniProtKB:Q05469

Function

diacylglycerol lipase activityGO:0120516
Substrates: diacylglycerol H2O
Products: monoacylglycerol fatty acid

Locations

lipid dropletGO:0005811 cytosolGO:0005829

Hydrolyzes diacylglycerol to monoacylglycerol and a fatty acid.

Part 4: monoacylglycerol hydrolysis
MGLL monoacylglycerol hydrolysisReactiontgl_mgll

Annotons

MGLL: monoglyceride lipase
mgll_activity
Participant: Family: monoglyceride lipase (MGLL)
Family:
monoglyceride lipase (MGLL)
Representative Members: MGLL (human)UniProtKB:Q99685

Function

monoacylglycerol lipase activityGO:0047372
Substrates: monoacylglycerol H2O
Products: glycerol fatty acid

Locations

cytosolGO:0005829

Hydrolyzes monoacylglycerol to glycerol and a fatty acid, completing lipolysis.