Affinage

PNPLA2

Patatin-like phospholipase domain-containing protein 2 · UniProt Q96AD5

Length
504 aa
Mass
55.3 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PNPLA2 (ATGL) is the rate-limiting triacylglycerol lipase that initiates intracellular lipolysis across adipose tissue, heart, liver, skeletal muscle, and pancreatic β-cells, and additionally functions as a transacylase catalyzing FAHFA biosynthesis (PMID:15337759, PMID:16752181, PMID:35676490). Its patatin-domain serine hydrolase activity is activated by the coactivator CGI-58/ABHD5—released from perilipin 1 upon PKA-mediated phosphorylation—and is stimulated by AMPK phosphorylation at S406 and zDHHC11-mediated S-acylation at C15, while inhibited by G0S2, FSP27, perilipin 5, UBXD8, and STX11 at the lipid droplet surface (PMID:19850935, PMID:21641555, PMID:39143266, PMID:20676045, PMID:24627478, PMID:23297223). ATGL protein turnover is controlled by COP1-mediated K48 polyubiquitination at K100 and a Golgi PtdIns4P–CUL7/FBXW8 ubiquitylation axis that couples glucose availability to lipolysis (PMID:27658392, PMID:38561547). Loss-of-function mutations in PNPLA2 cause neutral lipid storage disease with myopathy (NLSDM), and the fatty acids liberated by ATGL serve as endogenous ligands for PPARα/δ nuclear receptors to sustain mitochondrial oxidative metabolism and thermogenesis (PMID:17187067, PMID:21857651, PMID:24268737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 High

    The identity of the enzyme initiating triglyceride hydrolysis was unknown; cloning and expression of desnutrin/PNPLA2 established it as a patatin-domain lipase that increases TG hydrolysis when overexpressed, founding the field of ATGL biology.

    Evidence Ectopic overexpression in transfected cells with TG hydrolysis assay and EGFP-fusion confocal microscopy

    PMID:15337759

    Open questions at the time
    • Endogenous substrate specificity not determined
    • In vivo physiological role not established
    • Coactivator/corepressor requirements unknown
  2. 2006 High

    Whether ATGL had unique substrate specificity versus HSL was unclear; in vitro assays demonstrated that ATGL hydrolyzes TG but not DG, establishing its non-redundant role as the first step of lipolysis, and human genetic studies linked PNPLA2 mutations to NLSDM.

    Evidence In vitro lipase activity in Cos-7 cells with substrate specificity determination; human genetic sequencing with siRNA knockdown validation

    PMID:16752181 PMID:17187067

    Open questions at the time
    • Crystal structure of patatin domain not solved
    • Mechanism of LD targeting not resolved
  3. 2009 High

    How ATGL is activated at lipid droplets was unknown; studies showed that perilipin 1 sequesters the coactivator CGI-58 under basal conditions, and PKA-mediated perilipin phosphorylation releases CGI-58 to directly bind and stimulate ATGL on LDs, establishing the hormonal lipolysis cascade.

    Evidence Live-cell imaging, Co-IP, and FRET in adipocytes; FoxO1 promoter binding and transcriptional regulation studies

    PMID:19297333 PMID:19850935

    Open questions at the time
    • Structural basis of CGI-58–ATGL interaction unknown
    • Relative contribution of transcriptional vs. post-translational control not quantified
  4. 2011 High

    Multiple regulatory layers converged: AMPK was shown to directly phosphorylate ATGL at S406 to enhance activity; perilipin 5 was identified as an inhibitory LD scaffold releasing ATGL upon PKA phosphorylation; GBF1/Arf1/COPI was found to traffic ATGL to LDs; and ATGL-deficient hearts revealed that ATGL-liberated fatty acids serve as essential PPARα/δ ligands for mitochondrial biogenesis, with agonist rescue of lethal cardiomyopathy.

    Evidence In vitro AMPK phosphorylation with S406 mutagenesis; FRET/Co-IP for PLIN5; yeast two-hybrid/Co-IP for GBF1; whole-body and adipose-specific ATGL KO mice with PPARα agonist rescue

    PMID:21393244 PMID:21641555 PMID:21789191 PMID:21857651

    Open questions at the time
    • Kinase-phosphatase balance at S406 in vivo not defined
    • Whether PPARα vs PPARδ preference is tissue-specific not fully resolved
  5. 2012 Medium

    How LD coat proteins differentially regulate ATGL was unclear; studies demonstrated that patatin-domain missense mutations abolish catalysis while preserving LD localization (separating these functions), perilipin 1 directly inhibits ATGL activity in vitro while FSP27 limits ATGL presence on LDs, and contraction increases ATGL–CGI-58 association in skeletal muscle.

    Evidence Patient mutation structure-function analysis with rescue; in vitro TG hydrolase inhibition assays; Co-IP from stimulated skeletal muscle

    PMID:22990388 PMID:23204327 PMID:23408028

    Open questions at the time
    • Structural mechanism of perilipin 1 direct inhibition unknown
    • Quantitative stoichiometry of LD coat interactions not determined
  6. 2013 High

    Additional inhibitory and transcriptional mechanisms were identified: UBXD8 was shown to bind ATGL and displace CGI-58 at LDs via p97/VCP recruitment, insulin was found to suppress ATGL transcription through mTORC1–Egr1, and β-cell-specific ATGL KO revealed PPARδ (not PPARα) as the downstream mediator of ATGL-dependent mitochondrial function in islets.

    Evidence Co-IP and LD size assays for UBXD8; ATGL promoter reporter with Egr1 manipulation; β-cell-specific ATGL KO with PPARδ agonist rescue

    PMID:23297223 PMID:23858058 PMID:24268737

    Open questions at the time
    • Whether UBXD8 regulation is hormonally controlled not established
    • Identity of specific fatty acid species acting as PPAR ligands not determined
  7. 2014 High

    FSP27 was mapped to a core domain (aa 120–220) that directly binds and inhibits ATGL, and hepatic ATGL was shown to preferentially channel hydrolyzed FAs to β-oxidation and PPARα signaling independently of L-FABP.

    Evidence Domain deletion mapping with Co-IP; hepatic ATGL knockdown/overexpression in L-FABP KO mice

    PMID:24610891 PMID:24627478

    Open questions at the time
    • FA channeling mechanism without L-FABP not molecularly defined
    • FSP27 inhibition mechanism at atomic level unknown
  8. 2016 High

    AMPK phosphorylation of ATGL at S406 was validated in vivo using adipose-specific AMPK double KO mice, and COP1 was identified as the first E3 ligase targeting ATGL for K48-linked proteasomal degradation at K100.

    Evidence Adipose-specific AMPK α1/α2 double KO with S406 phosphorylation analysis; COP1 Co-IP, ubiquitination assay with K100 mutagenesis, in vivo HFD rescue

    PMID:27185873 PMID:27658392

    Open questions at the time
    • Whether COP1 and AMPK pathways are coordinated not tested
    • Deubiquitinase for ATGL not identified
  9. 2019 Medium

    Beyond hydrolysis, ATGL was shown to possess transacylase activity, transferring acyl groups between DAG molecules to form TG plus MAG, providing an alternative lipolytic route when HSL is absent.

    Evidence Radiolabeled DAG transacylation assay with HSL-deficient LD fractions and Atglistatin inhibitor

    PMID:31035700

    Open questions at the time
    • Physiological significance of transacylation in HSL-sufficient cells unclear
    • Structural basis for dual hydrolase/transacylase activity unknown
  10. 2022 High

    ATGL's transacylase activity was shown to be the principal biosynthetic enzyme for FAHFAs, a bioactive lipid class, with adipose-specific KO reducing FAHFA levels by 80–90%; separately, STX11 was identified as a new inhibitor that retains ATGL in the ER to prevent LD translocation.

    Evidence Recombinant ATGL transacylation assay with catalytic-dead mutant; adipose-specific ATGL KO FAHFA quantification; STX11 Co-IP with domain mapping and localization imaging

    PMID:35372814 PMID:35676490

    Open questions at the time
    • FAHFA transacylation substrate selectivity rules not defined
    • How STX11 vs GBF1 pathways coordinate ATGL trafficking unclear
  11. 2024 High

    Two new regulatory axes were revealed: zDHHC11-mediated S-acylation at C15 was shown to be required for ATGL catalytic activity (not LD localization), and a Golgi PtdIns4P–CUL7/FBXW8 ubiquitylation pathway was identified as a glucose-sensing mechanism controlling ATGL protein levels and lipolysis; additionally, PNPLA3(I148M) was shown to cause steatosis by sequestering ABHD5 from ATGL.

    Evidence C15 mutagenesis with S-acylation assay in hepatocytes and mice; Golgi PtdIns4P manipulation with CUL7/FBXW8 assembly and ATGL ubiquitylation assays including ex vivo human liver; NanoBiT and in vitro reconstitution for PNPLA3–ABHD5–ATGL axis

    PMID:38561547 PMID:39143266 PMID:39550037

    Open questions at the time
    • How S-acylation at C15 enables catalysis structurally is unknown
    • Interplay between COP1 and CUL7/FBXW8 ubiquitylation pathways not resolved
    • Full-length ATGL structure remains unsolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length ATGL (with and without CGI-58) is needed to explain how S-acylation at C15 enables catalysis, how the patatin domain coordinates hydrolase vs. transacylase activities, and how multiple inhibitory proteins (G0S2, FSP27, PLIN1, UBXD8, STX11) achieve non-redundant regulation at the LD surface.
  • No atomic-resolution structure of ATGL or ATGL–CGI-58 complex
  • Deubiquitinase(s) for ATGL not identified
  • How specific FA species from ATGL hydrolysis are channeled to PPARα vs PPARδ remains undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0008289 lipid binding 2 GO:0016740 transferase activity 2
Localization
GO:0005811 lipid droplet 5 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ABHD5CIDECG0S2GBF1PLIN1PLIN5STX11UBXD8

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Desnutrin/PNPLA2 encodes a patatin-domain-containing protein that, when overexpressed, increases triglyceride hydrolysis in cells; it localizes to the cytoplasm as shown by confocal microscopy of EGFP-tagged protein. Ectopic overexpression in transfected cells with triglyceride hydrolysis assay; confocal microscopy of EGFP-fusion protein The Journal of biological chemistry High 15337759
2006 Mutations in PNPLA2 (ATGL) cause neutral lipid storage disease with myopathy (NLSDM); truncating mutations preserve the patatin catalytic domain but disrupt the hydrophobic domain, and siRNA knockdown of ATGL mimics the triglyceride degradation block. Human genetic sequencing; siRNA knockdown with lipid accumulation assay Nature genetics High 17187067
2006 Human PNPLA2/ATGL has triglyceride hydrolase activity but lacks diglyceride hydrolase activity in vitro, distinguishing it from HSL; this was demonstrated by transfecting Cos-7 cells with ATGL cDNA and measuring tri- and diglyceride hydrolase activities. In vitro lipase activity assay in transfected Cos-7 cells; selective HSL inhibitor controls Diabetologia High 16752181
2009 Perilipin (PLIN1) sequesters CGI-58 (ABHD5) with high affinity under basal conditions, suppressing its interaction with ATGL; PKA-mediated phosphorylation of perilipin at S492 or S517 releases CGI-58, allowing it to directly interact with ATGL primarily on lipid droplets to stimulate lipolysis. Live-cell protein trafficking imaging; co-immunoprecipitation; FRET-based interaction assays in adipocytes The Journal of biological chemistry High 19850935
2009 FoxO1 directly binds to the ATGL promoter at two FoxO1-binding sites and activates ATGL transcription; insulin controls FoxO1 nucleo-cytoplasmic shuttling to regulate ATGL expression and thereby basal and stimulated lipolysis in adipocytes. Luciferase reporter assay with ATGL promoter; FoxO1 knockdown in 3T3-L1 adipocytes; lentiviral FoxO1 overexpression; ChIP-implied promoter analysis The Journal of biological chemistry High 19297333
2010 The C-terminal hydrophobic domain of ATGL is required for lipid droplet targeting and CGI-58-independent lipid droplet degradation; CGI-58 can partially rescue LD turnover by an ATGL mutant lacking this domain. G0S2 inhibits ATGL activity by directly binding ATGL independently of its activity state or CGI-58 presence, and cannot be overridden by combined CGI-58/ATGL expression. Loss-of-function ATGL C-terminal deletion mutants; co-expression experiments; LD morphology analysis; G0S2 binding assays Cell cycle (Georgetown, Tex.) Medium 20676045
2011 ATGL-mediated lipolysis generates lipid ligands required for PPAR-α and PPAR-δ activation; in ATGL-deficient mouse hearts, decreased PPAR-α/δ signaling leads to reduced PGC-1α/β expression, disrupted mitochondrial oxidation, and lethal cardiomyopathy, all of which are fully rescued by pharmacological PPAR-α agonist treatment. Whole-body ATGL knockout mice; PPAR-α agonist rescue experiments; mitochondrial respiration assays; gene expression analysis; cardiac function assessment Nature medicine High 21857651
2011 ATGL (desnutrin) is phosphorylated by AMPK at serine 406, which increases its TAG hydrolase activity; adipose-specific ATGL ablation converts brown adipose tissue to a WAT-like phenotype with severely impaired thermogenesis and decreased PPARα binding to the UCP-1 promoter. In vitro AMPK phosphorylation assay; S406 phospho-site mutagenesis; adipose-specific ATGL knockout mice; thermogenesis and gene expression analysis Cell metabolism High 21641555
2011 Perilipin 5 (LSDP5) directly interacts with ATGL (via FRET/FRAP and Co-IP) and recruits ATGL to lipid droplet surfaces, but unlike CGI-58, this interaction decreases lipolysis; PKA phosphorylation of perilipin 5 releases ATGL-mediated lipolysis. Neither perilipin 1 nor 2 interacted directly with ATGL. Anisotropy FRET, Co-immunoprecipitation, [32P]orthophosphate radiolabeling, lipolysis assay in cell culture The Journal of biological chemistry High 21393244
2011 SIRT1 controls ATGL transcription by deacetylating FoxO1, which then directly binds the ATGL promoter to regulate its expression; SIRT1 knockdown reduces ATGL transcription and attenuates lipolysis in cultured adipocytes. shRNA knockdown of SIRT1; FoxO1 acetylation assay; ATGL promoter-driven reporter assay; lipolysis measurement Journal of lipid research Medium 21743036
2011 GBF1 (Arf1 exchange factor) directly interacts with ATGL through multiple contact sites: the ATGL C-terminal region binds the GBF1 Sec7 domain, and the patatin domain of ATGL binds GBF1 HDS1 and HDS2 domains; GBF1/Arf1/COPI pathway is required for ATGL delivery to lipid droplets. Yeast two-hybrid; Co-immunoprecipitation in mammalian cells; direct protein-binding assays; LD localization imaging PloS one Medium 21789191
2013 UBXD8 directly binds ATGL and promotes dissociation of its coactivator CGI-58, thereby inhibiting ATGL activity and increasing lipid droplet size; UBXD8 is restricted to the ER by UBAC2, and its trafficking to LDs recruits p97/VCP to control ATGL-mediated triglyceride hydrolysis. Co-immunoprecipitation; UBXD8/UBAC2 expression manipulation; LD size measurement; triglyceride hydrolysis assay Proceedings of the National Academy of Sciences of the United States of America High 23297223
2013 Insulin inhibits lipolysis via an mTORC1-Egr1-ATGL pathway: mTORC1 promotes Egr1 expression (via 4E-BP-mediated translation), and Egr1 directly inhibits the ATGL promoter in vitro and ATGL expression in adipocytes, reducing lipolysis. Yeast genetic screen (Msn4/Tor1 ortholog identification); luciferase reporter assay with ATGL promoter; Egr1 knockdown/overexpression in adipocytes; mTORC1 inhibitors; high-fat diet mouse model Molecular and cellular biology High 23858058
2013 ATGL-catalyzed lipolysis in pancreatic β-cells generates PPARδ ligands that maintain mitochondrial oxidative function required for glucose-stimulated insulin secretion; β-cell-specific ATGL ablation impairs mitochondrial respiration and ATP production, and PPARδ agonist (but not PPARα) restores this defect. β-cell-specific ATGL KO mice; glucose-stimulated insulin secretion assay; mitochondrial respiration; PPARδ agonist rescue; adenoviral ATGL re-expression in KO islets Cell metabolism High 24268737
2014 FSP27 (fat-specific protein 27) directly interacts with ATGL through a core domain (amino acids 120-220) to inhibit ATGL lipolytic function and promote triglyceride storage; FSP27 depletion increases lipolysis via ATGL, leading to FFA-induced inhibition of insulin signaling. Co-immunoprecipitation; FSP27 domain deletion mapping; FSP27 knockdown; ATGL KO mouse fibroblasts; lipolysis and AKT phosphorylation assays in human adipocytes The Journal of biological chemistry High 24627478
2014 Hepatic ATGL preferentially channels hydrolyzed fatty acids to β-oxidation and induces PPARα signaling through an L-FABP-independent mechanism, as shown by ATGL knockdown/overexpression in L-FABP KO mice and primary hepatocytes. Adenovirus-mediated hepatic ATGL knockdown/overexpression; L-FABP KO mice; FA oxidation assay in primary hepatocytes; PPARα target gene expression Journal of lipid research Medium 24610891
2016 AMPK phosphorylates ATGL (desnutrin) at S406 in vivo to increase its TAG hydrolase activity and promote basal lipolysis in adipose tissue; adipose-specific AMPK double KO mice show defective ATGL S406 phosphorylation and reduced basal lipolysis. Adipose-specific AMPK (α1/α2) double knockout mice; S406 phosphorylation analysis; TAG hydrolase activity assay; adipocyte lipolysis measurement Molecular and cellular biology High 27185873
2016 E3 ubiquitin ligase COP1 (RFWD2) binds the consensus VP motif of ATGL and targets it for proteasomal degradation via K48-linked polyubiquitination predominantly at lysine 100; COP1 depletion by adenovirus in mice ameliorates high-fat diet-induced hepatic steatosis. Co-immunoprecipitation; ubiquitination assay with K48 linkage specificity; site-directed mutagenesis (K100); adenovirus-mediated COP1 knockdown in HFD mice; hepatic TG measurement Diabetes High 27658392
2019 ATGL functions as a transacylase when HSL is deficient: it transfers an acyl group from one DAG to another, forming TG plus monoglyceride, providing an alternative lipolytic pathway; this transacylase activity was demonstrated using radiolabeled DAG substrates with HSL-deficient lipid droplet fractions and ATGL-specific inhibitor. Radiolabeled DAG hydrolysis/transacylation assay with lipid droplet fractions from HSL-deficient adipose tissue; ATGL-specific inhibitor (Atglistatin) Cells Medium 31035700
2020 OSBPL2 (ORP2) links the ER with lipid droplets, binds COPB1, and mediates ATGL transport from the ER to the LD surface; loss of OSBPL2 impairs ATGL translocation and lipid droplet lipolysis. Co-immunoprecipitation; OSBPL2 knockout; LD lipolysis assay; localization imaging iScience Medium 32650117
2022 ATGL catalyzes a transacylation reaction to biosynthesize fatty acid esters of hydroxy fatty acids (FAHFAs): it uses TG or DG as acyl donors to esterify hydroxy fatty acids. Overexpression of wild-type but not catalytically dead ATGL increases FAHFA biosynthesis; adipose-specific ATGL KO reduces endogenous FAHFA and FAHFA-TG levels by 80-90%. Recombinant ATGL transacylation assay in vitro; catalytically dead mutant overexpression; adipose-specific ATGL KO mice; chemical biology/proteomics identification; DGAT activity manipulation Nature High 35676490
2022 STX11 (syntaxin-11) directly binds ATGL through its C-terminus interacting with the patatin domain of ATGL, prevents ATGL spatial translocation to LDs by recruiting it to the ER, and thereby inhibits lipid droplet degradation and lipophagy; STX11 deficiency promotes ATGL-SIRT1 signaling to enhance lipophagy. Co-immunoprecipitation with domain mapping; STX11 overexpression/knockdown; LD degradation assay; ATGL localization imaging iScience Medium 35372814
2024 zDHHC11 S-acylates ATGL at cysteine 15; preventing S-acylation at C15 renders ATGL catalytically inactive despite proper lipid droplet localization, causing LD accumulation and defective lipolysis/lipophagy. zDHHC11 overexpression reduces LD size; its elimination enlarges LDs. zDHHC11 KO/overexpression; C15 ATGL mutagenesis; lipolysis assay; LD morphology; S-acylation biochemical assay in hepatocyte cultures and mice Nature metabolism High 39143266
2024 PNPLA3(I148M) promotes hepatic steatosis by accumulating on lipid droplets and sequestering ABHD5 away from ATGL, thereby inhibiting ATGL-mediated TG hydrolysis in an ABHD5-dependent gain-of-function mechanism; ABHD5 overexpression reverses steatosis in Pnpla3M/M mice, and PNPLA3 (like ATGL) is activated by ABHD5 in vitro. NanoBiT complementation assay for protein interactions in hepatocytes; immunocytochemistry; in vitro TG hydrolase activity with purified recombinant proteins; liver-specific Atgl KO mice expressing PNPLA3; AAV-ABHD5 rescue in Pnpla3M/M mice Journal of hepatology High 39550037
2024 Intracellular glucose depletion reduces Golgi PtdIns4P levels, decreasing assembly of the CUL7FBXW8 E3 ligase complex in the Golgi, which leads to reduced polyubiquitylation of ATGL and enhanced ATGL-driven lipolysis; this Golgi PtdIns4P-CUL7FBXW8-ATGL axis constitutes a cell-intrinsic glucose-sensing mechanism controlling lipolysis. Golgi PtdIns4P manipulation; CUL7FBXW8 complex assembly assay; ATGL ubiquitylation assay; genetic/pharmacological manipulation in mouse steatosis models and ex vivo human liver perfusion Nature cell biology High 38561547
2007 PEDF (pigment epithelium-derived factor) co-immunoprecipitates with ATGL in hepatic lysates and functions as a receptor-ligand interaction that regulates hepatocyte triglyceride content; PEDF-null hepatocytes have increased TG content that is rescued by recombinant PEDF in an ATGL-dependent manner. Co-immunoprecipitation; ATGL inhibitor ((R)-bromoenol lactone); rPEDF treatment of PEDF-null hepatocytes; TG content measurement; immunofluorescence localization Journal of hepatology Medium 18191271
2012 ATGL missense mutations (p.Arg221Pro, p.Asn172Lys) within or proximal to the patatin domain result in proteins with near-absent lipolytic activity that still localize correctly to lipid droplets; wild-type ATGL overexpression in patient fibroblasts corrects the metabolic defect and reduces LD accumulation, demonstrating that LD-binding and catalytic activity are separable functions. ATGL mutant expression in patient fibroblasts; lipid droplet localization imaging; lipolytic activity assay; WT ATGL rescue overexpression Human molecular genetics Medium 22990388
2012 In skeletal muscle, the ATGL-CGI-58 interaction increases 128% following contraction-induced lipolysis; ATGL interacts with PLIN2, PLIN3, and PLIN5 at rest, but PLIN2-ATGL interaction decreases during stimulation, suggesting PLINs regulate lipolysis by controlling ATGL-CGI-58 association at the lipid droplet surface. Co-immunoprecipitation from isolated rat soleus at rest vs. tetanic stimulation; quantitative interaction analysis American journal of physiology. Regulatory, integrative and comparative physiology Medium 23408028
2012 Distinct mechanisms regulate ATGL-mediated lipolysis by LD coat proteins: perilipin 1 directly inhibits ATGL triacylglycerol hydrolase activity in vitro and attenuates CGI-58-dependent ATGL activation, whereas FSP27 constitutively limits ATGL presence on LDs. Isoproterenol-stimulated ATGL translocation to LDs requires perilipin 1. In vitro TG hydrolase activity assay; perilipin/FSP27 knockdown; ATGL overexpression; LD morphology and ATGL localization imaging in adipocytes Molecular endocrinology (Baltimore, Md.) Medium 23204327
2017 Lipid droplet-associated hydrolase (LDAH) enhances K48-linked polyubiquitination and proteasomal degradation of ATGL, promoting TAG accumulation; co-expression of ATGL reverses LDAH-induced LD phenotype changes. LDAH overexpression/knockdown; pulse-chase TAG turnover assay; ubiquitination assay; ATGL co-expression rescue; LD morphology analysis Scientific reports Medium 28578400
2008 ATGL protein is expressed in human skeletal muscle exclusively in type I (oxidative) fibers, as demonstrated by immunohistochemical and immunofluorescent staining of vastus lateralis muscle biopsies, indicating a fiber-type specific role in intramuscular fatty acid handling. Immunohistochemistry and immunofluorescence on human skeletal muscle biopsies with fiber-type co-staining Histochemistry and cell biology Medium 18224330
2015 ATGL overexpression in skeletal muscle myotubes increases lipolysis, activates PPARδ transcriptional activity, and enhances mitochondrial oxidative capacity; these transcriptional responses are specific to ATGL-mediated lipolysis and not a generalized increase in fatty acid flux. Adenoviral and AAV-mediated ATGL overexpression in C2C12 myotubes and mouse tibialis anterior; PPARδ reporter assay; mitochondrial respiration measurement American journal of physiology. Endocrinology and metabolism Medium 25852007

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nature medicine 641 21857651
2004 Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. The Journal of biological chemistry 502 15337759
2011 Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell metabolism 428 21641555
2006 The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nature genetics 382 17187067
2009 Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). The Journal of biological chemistry 312 19850935
2009 Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. American journal of physiology. Endocrinology and metabolism 238 19401457
2011 Unique regulation of adipose triglyceride lipase (ATGL) by perilipin 5, a lipid droplet-associated protein. The Journal of biological chemistry 229 21393244
2016 AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue. Molecular and cellular biology 226 27185873
2013 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences of the United States of America 193 23297223
2009 FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. The Journal of biological chemistry 186 19297333
2018 Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation. Molecular cancer 174 29764424
2006 The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma. American journal of physiology. Endocrinology and metabolism 168 16705060
2008 Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. Journal of lipid research 163 19050316
2015 Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice. Endocrinology 158 26196542
2011 SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. Journal of lipid research 154 21743036
2018 Of mice and men: The physiological role of adipose triglyceride lipase (ATGL). Biochimica et biophysica acta. Molecular and cell biology of lipids 138 30367950
2013 Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Molecular and cellular biology 131 23858058
2007 Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). Journal of hepatology 112 18191271
2013 Desnutrin/ATGL activates PPARδ to promote mitochondrial function for insulin secretion in islet β cells. Cell metabolism 103 24268737
2022 ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature 102 35676490
2014 Fat-specific protein 27 (FSP27) interacts with adipose triglyceride lipase (ATGL) to regulate lipolysis and insulin sensitivity in human adipocytes. The Journal of biological chemistry 100 24627478
2016 LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL). Scientific reports 96 27759039
2012 Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) deficiencies affect expression of lipolytic activities in mouse adipose tissues. Molecular & cellular proteomics : MCP 96 22984285
2010 Differential control of ATGL-mediated lipid droplet degradation by CGI-58 and G0S2. Cell cycle (Georgetown, Tex.) 95 20676045
2012 Fasting energy homeostasis in mice with adipose deficiency of desnutrin/adipose triglyceride lipase. Endocrinology 86 22374972
2014 Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia. Hepatology (Baltimore, Md.) 85 24002947
2022 ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. Cell reports 83 35675775
2015 PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase. Cell reports 81 25753422
2011 The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene. Journal of neurology 81 21544567
2013 Skeletal muscle PLIN proteins, ATGL and CGI-58, interactions at rest and following stimulated contraction. American journal of physiology. Regulatory, integrative and comparative physiology 76 23408028
2006 Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia 76 16752181
2018 Hints on ATGL implications in cancer: beyond bioenergetic clues. Cell death & disease 70 29472527
2014 Lipid droplet protein LID-1 mediates ATGL-1-dependent lipolysis during fasting in Caenorhabditis elegans. Molecular and cellular biology 70 25202121
2015 Inhibition of adipose triglyceride lipase (ATGL) by the putative tumor suppressor G0S2 or a small molecule inhibitor attenuates the growth of cancer cells. Oncotarget 69 26318046
2015 Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity. Proceedings of the National Academy of Sciences of the United States of America 67 26508640
2012 Fenofibrate lowers lipid accumulation in myotubes by modulating the PPARα/AMPK/FoxO1/ATGL pathway. Biochemical pharmacology 63 22687626
2016 ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2. Autophagy 58 27559856
2016 Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation. Diabetes 58 27658392
2020 The novel non-steroidal MR antagonist finerenone improves metabolic parameters in high-fat diet-fed mice and activates brown adipose tissue via AMPK-ATGL pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 32729974
2018 Coordination Among Lipid Droplets, Peroxisomes, and Mitochondria Regulates Energy Expenditure Through the CIDE-ATGL-PPARα Pathway in Adipocytes. Diabetes 56 29986925
2008 Adipose triglyceride lipase (ATGL) expression in human skeletal muscle is type I (oxidative) fiber specific. Histochemistry and cell biology 56 18224330
2011 Interaction between the triglyceride lipase ATGL and the Arf1 activator GBF1. PloS one 54 21789191
2014 A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: a case report and literature review. Neuromuscular disorders : NMD 50 24836204
2010 Neutral lipid storage disease with subclinical myopathy due to a retrotransposal insertion in the PNPLA2 gene. Neuromuscular disorders : NMD 48 20471263
2018 Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53. Oncogene 47 30367149
2012 Contribution of novel ATGL missense mutations to the clinical phenotype of NLSD-M: a strikingly low amount of lipase activity may preserve cardiac function. Human molecular genetics 47 22990388
2008 Developmental, hormonal, and nutritional regulation of porcine adipose triglyceride lipase (ATGL). Lipids 46 18189154
2016 A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice. Diabetologia 45 27677764
2015 ATGL-mediated triglyceride turnover and the regulation of mitochondrial capacity in skeletal muscle. American journal of physiology. Endocrinology and metabolism 42 25852007
2012 Distinct mechanisms regulate ATGL-mediated adipocyte lipolysis by lipid droplet coat proteins. Molecular endocrinology (Baltimore, Md.) 42 23204327
2010 17beta-estradiol supplementation attenuates ovariectomy-induced increases in ATGL signaling and reduced perilipin expression in visceral adipose tissue. Journal of cellular biochemistry 41 20336671
2008 Distal lipid storage myopathy due to PNPLA2 mutation. Neuromuscular disorders : NMD 41 18657972
2016 Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation. Cell reports 39 27396333
2015 Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings. Molecular genetics and metabolism 39 25956450
2014 Hepatic ATGL mediates PPAR-α signaling and fatty acid channeling through an L-FABP independent mechanism. Journal of lipid research 39 24610891
2024 PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. Journal of hepatology 38 39550037
2017 Epistatic interaction between the lipase-encoding genes Pnpla2 and Lipe causes liposarcoma in mice. PLoS genetics 37 28459858
2017 Atgl deficiency induces podocyte apoptosis and leads to glomerular filtration barrier damage. The FEBS journal 36 28194887
2015 ATGL and CGI-58 are lipid droplet proteins of the hepatic stellate cell line HSC-T6. Journal of lipid research 36 26330055
2013 ERα regulates lipid metabolism in bone through ATGL and perilipin. Journal of cellular biochemistry 36 23296636
2017 Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator-activated receptor γ (PPARγ) during adipocyte differentiation. The Journal of biological chemistry 34 28726642
2015 PEDF and PEDF-derived peptide 44mer stimulate cardiac triglyceride degradation via ATGL. Journal of translational medicine 33 25890298
2009 Regulation of ATGL expression mediated by leptin in vitro in porcine adipocyte lipolysis. Molecular and cellular biochemistry 33 19626423
2019 Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy. JCI insight 32 31185001
2016 PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 27485820
2016 Comparative proteomics reveals abnormal binding of ATGL and dysferlin on lipid droplets from pressure overload-induced dysfunctional rat hearts. Scientific reports 31 26795240
2014 Inhibition of age-related cytokines production by ATGL: a mechanism linked to the anti-inflammatory effect of resveratrol. Mediators of inflammation 31 24817795
2020 Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation. American journal of physiology. Heart and circulatory physiology 30 33185110
2012 Distinct roles for alpha-beta hydrolase domain 5 (ABHD5/CGI-58) and adipose triglyceride lipase (ATGL/PNPLA2) in lipid metabolism and signaling. Adipocyte 29 23145367
2021 Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity. Oncogenesis 28 34845203
2020 OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis. iScience 28 32650117
2006 Application of a sensitive collection heuristic for very large protein families: evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases. BMC bioinformatics 28 16551354
2019 ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans. Molecular metabolism 27 31311719
2024 S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes. Nature metabolism 26 39143266
2024 Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. Journal of hepatology 26 39357546
2012 Subclinical myopathy in a child with neutral lipid storage disease and mutations in the PNPLA2 gene. Biochemical and biophysical research communications 26 23146629
2021 Loss of ephrin B2 receptor (EPHB2) sets lipid rheostat by regulating proteins DGAT1 and ATGL inducing lipid droplet storage in prostate cancer cells. Laboratory investigation; a journal of technical methods and pathology 25 33824421
2019 An Epistatic Interaction between Pnpla2 and Lipe Reveals New Pathways of Adipose Tissue Lipolysis. Cells 25 31035700
2015 A myopathy with unusual features caused by PNPLA2 gene mutations. Muscle & nerve 25 25287355
2015 4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL. The Journal of biological chemistry 25 25814662
2012 Higher levels of ATGL are associated with exercise-induced enhancement of lipolysis in rat epididymal adipocytes. PloS one 25 22815850
2010 A novel PNPLA2 mutation causes neutral lipid storage disease with myopathy (NLSDM) presenting muscular dystrophic features with lipid storage and rimmed vacuoles. Clinical neuropathology 25 21073837
2024 Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL. Nature cell biology 24 38561547
2017 Late onset of neutral lipid storage disease due to novel PNPLA2 mutations causing total loss of lipase activity in a patient with myopathy and slight cardiac involvement. Neuromuscular disorders : NMD 24 28258942
2022 The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy. iScience 23 35372814
2022 Recent Advances on the Role of ATGL in Cancer. Frontiers in oncology 23 35912266
2021 Long non-coding RNA NEAT1 facilitates the growth, migration, and invasion of ovarian cancer cells via the let-7 g/MEST/ATGL axis. Cancer cell international 23 34416900
2017 Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma. Anticancer research 23 28179319
2017 Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation. Scientific reports 23 28578400
2016 Depletion of Rab32 decreases intracellular lipid accumulation and induces lipolysis through enhancing ATGL expression in hepatocytes. Biochemical and biophysical research communications 23 26882978
2016 Reduced ATGL-mediated lipolysis attenuates β-adrenergic-induced AMPK signaling, but not the induction of PKA-targeted genes, in adipocytes and adipose tissue. American journal of physiology. Cell physiology 23 27357546
2024 Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides. Brain, behavior, and immunity 22 39326768
2023 Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis. Cell death & disease 22 36746922
2020 Effect of salt promote the muscle triglyceride hydrolysis during dry-salting by inducing the phosphorylation of adipose tissue triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) and lipid droplets splitting. Food chemistry 22 32454271
2019 Hedgehog signaling promotes lipolysis in adipose tissue through directly regulating Bmm/ATGL lipase. Developmental biology 22 31550483
2021 Palmitate induces fat accumulation via repressing FoxO1-mediated ATGL-dependent lipolysis in HepG2 hepatocytes. PloS one 21 33449950
2012 Novel PNPLA2 gene mutations in Chinese Han patients causing neutral lipid storage disease with myopathy. Journal of human genetics 21 22832386
2012 Symptomatic lipid storage in carriers for the PNPLA2 gene. European journal of human genetics : EJHG 21 23232698
2025 ATGL regulates renal fibrosis by reprogramming lipid metabolism during the transition from AKI to CKD. Molecular therapy : the journal of the American Society of Gene Therapy 20 39748508
2021 Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY. Redox biology 20 33450726