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Showing PNPLA2 — ATGL is a alias.

PNPLA2

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

Length
504 aa
Mass
55.3 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PNPLA2 (desnutrin/ATGL) is the rate-limiting triacylglycerol hydrolase that initiates intracellular lipolysis, mobilizing fatty acids from lipid droplets via a patatin-like domain whose minimal catalytically active fragment extends beyond the canonical patatin region to Leu254 (PMID:15337759, PMID:17187067, PMID:22039468). Loss-of-function mutations sparing the active site but truncating the hydrophobic domain cause neutral lipid storage disease with myopathy (NLSDM), and ATGL deficiency drives lethal cardiomyopathy that is reversed by PPAR-α agonism, because ATGL-liberated fatty acids serve as ligands that activate PPAR-α/δ and PGC-1α/β-driven mitochondrial oxidative metabolism (PMID:17187067, PMID:21857651). Beyond canonical hydrolysis, ATGL catalyzes transacylation reactions that generate FAHFA lipid species and, when HSL is absent, form triglyceride from diacylglycerol (PMID:35676490, PMID:31035700). Its activity is tightly governed: co-activated by CGI-58/ABHD5 through a defined protein interface and inhibited by G0S2, FSP27, and perilipin 1 (PMID:22039468, PMID:20676045, PMID:24627478, PMID:23204327, PMID:32542055), activated by AMPK phosphorylation at S406 (PMID:21641555, PMID:27185873), and dependent on zDHHC11-mediated S-acylation at Cys15 for catalysis (PMID:39143266). ATGL is targeted to lipid droplets through its C-terminal hydrophobic domain and GBF1/Arf1/COPI trafficking, and is restrained by ER-tethering via STX11 and by ubiquitin-proteasomal turnover through CUL7ᶠᵇˣʷ⁸, COP1/PEDF, and LDAH (PMID:20676045, PMID:21789191, PMID:38561547, PMID:30926171, PMID:28578400, PMID:35372814). Transcriptionally, ATGL is induced by FoxO1 (deacetylated by SIRT1) and PPARγ and repressed by insulin via mTORC1–Egr1 signaling (PMID:19297333, PMID:16705060, PMID:23858058, PMID:21743036). Through these outputs ATGL links lipolysis to oxidative metabolism via SIRT1–PGC-1α, controls glucose-stimulated insulin secretion via PPARδ in β-cells, and regulates adipocyte glucose uptake by promoting TXNIP degradation (PMID:25614670, PMID:24268737, PMID:33508319).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    Established that PNPLA2 encodes a patatin-domain protein with intrinsic triglyceride hydrolase activity, defining the gene product as a lipase.

    Evidence Ectopic overexpression with TG hydrolysis assay and EGFP localization in transfected cells

    PMID:15337759

    Open questions at the time
    • Did not establish in vivo physiological role
    • Catalytic residues and regulators unidentified
  2. 2006 High

    Showed PNPLA2 is the rate-limiting TG hydrolase in vivo and that its loss causes a human disease, connecting biochemistry to pathology.

    Evidence Patient mutation analysis (NLSDM) plus siRNA knockdown with lipid accumulation; insulin/TNF-α promoter regulation by reporter assay

    PMID:16705060 PMID:17187067

    Open questions at the time
    • Downstream metabolic consequences of fatty-acid liberation not defined
    • Co-activators and inhibitors not yet identified
  3. 2009 High

    Identified transcriptional control of ATGL by FoxO1, explaining hormonal regulation of lipolytic capacity.

    Evidence ChIP, luciferase reporter, siRNA knockdown and lipolysis assay in adipocytes

    PMID:19297333

    Open questions at the time
    • Did not address post-translational regulation
    • Interplay with other transcription factors unresolved
  4. 2010 Medium

    Defined direct protein inhibitors (G0S2, UBXD8) and the C-terminal LD-targeting domain, establishing that ATGL activity and localization are governed by distinct interactions.

    Evidence Co-IP, direct binding, domain deletion mutagenesis and LD morphology assays

    PMID:20676045 PMID:23297223

    Open questions at the time
    • Structural basis of inhibitor binding not resolved
    • Single-lab Co-IP for some interactions
  5. 2011 High

    Connected ATGL-derived lipid ligands to PPAR/PGC-1α-driven mitochondrial metabolism and defined AMPK phosphorylation at S406 as an activating modification, explaining the cardiomyopathy and thermogenic phenotypes.

    Evidence Atgl-KO and adipose-specific KO mice, mitochondrial respiration, PPAR-α agonist rescue, phosphosite mutagenesis and kinase assay

    PMID:21641555 PMID:21857651

    Open questions at the time
    • Identity of the specific ligand lipid species not defined
    • How phosphorylation alters catalysis mechanistically unclear
  6. 2011 High

    Mapped the minimal catalytic domain to Leu254 and showed it suffices for CGI-58 co-activation and G0S2 inhibition, localizing regulation to a defined region.

    Evidence Truncation mutagenesis, in vitro lipase assay, binding assay, homology modeling

    PMID:22039468

    Open questions at the time
    • No experimental crystal structure
    • Role of the C-terminal region in vivo not fully resolved
  7. 2011 Medium

    Linked SIRT1 deacetylation of FoxO1 to ATGL transcription, integrating energy/NAD+ status with lipolytic gene expression.

    Evidence shRNA knockdown, lipolysis and gene expression assays in adipocytes

    PMID:21743036

    Open questions at the time
    • Direct demonstration of FoxO1 acetylation at the ATGL promoter limited
    • Single-lab study
  8. 2011 Medium

    Identified GBF1/Arf1/COPI trafficking as a route delivering ATGL to lipid droplets, defining a transport mechanism.

    Evidence Yeast two-hybrid, Co-IP, direct binding and localization of GBF1 domain fragments

    PMID:21789191

    Open questions at the time
    • Physiological contribution of this route versus C-terminal targeting unquantified
    • Single-lab interaction data
  9. 2012 High

    Distinguished perilipin 1 as a direct in vitro inhibitor and obligate translocation factor versus FSP27's constitutive restriction, refining the LD-surface regulatory hierarchy.

    Evidence In vitro TAG hydrolase assay, siRNA, LD translocation imaging

    PMID:23204327

    Open questions at the time
    • Structural basis of perilipin1–ATGL inhibition not defined
  10. 2013 High

    Extended the regulatory network with FSP27 direct binding, mTORC1–Egr1 insulin repression, and a β-cell PPARδ lipolytic-signaling axis controlling insulin secretion.

    Evidence Co-IP/domain mapping, yeast screen with promoter binding, β-cell-specific KO with PPARδ agonist rescue and contraction-state muscle Co-IP

    PMID:23408028 PMID:23858058 PMID:24268737 PMID:24627478

    Open questions at the time
    • Tissue-specific differences in regulator usage not fully mapped
    • Some interaction data from single labs
  11. 2015 Medium

    Established SIRT1 as a node downstream of ATGL lipolysis driving PGC-1α/PPAR-α oxidative transcription independent of NAD+, clarifying signal-to-transcription coupling.

    Evidence ATGL gain/loss, SIRT1 deacetylase activity assay, β-adrenergic stimulation

    PMID:25614670

    Open questions at the time
    • Mechanism by which a lipid product activates SIRT1 unresolved
    • Single-lab study
  12. 2016 High

    Provided in vivo proof that AMPK phosphorylates and activates ATGL at S406 and defined reciprocal ATGL-dependent G0S2 protein stabilization, closing loops in activity regulation.

    Evidence Adipose-specific AMPK double-KO mice, phosphorylation and TAG hydrolase assays; G0S2 K25 ubiquitination mutagenesis with Atgl-KO tissue

    PMID:27185873 PMID:27248498

    Open questions at the time
    • Whether AMPK acts directly on ATGL in vivo versus via other kinases not fully excluded
  13. 2017 High

    Defined ubiquitin-proteasomal turnover (LDAH-enhanced) and a tumor-suppressive epistasis with HSL whose dual loss causes liposarcoma, linking lipolytic capacity to proliferation control.

    Evidence Ubiquitination/pulse-chase assays; adipose-specific ATGL/HSL double-KO mouse with tumor histology

    PMID:28459858 PMID:28578400

    Open questions at the time
    • Mechanism linking lipid accumulation to tumorigenesis not defined
    • E3 ligase for LDAH-driven turnover not identified here
  14. 2019 Medium

    Revealed ATGL transacylase activity (DG-to-TG when HSL is absent), nuclear COP1/PEDF degradation, and tissue-specific intestinal substrate pools, broadening its enzymatic and regulatory repertoire.

    Evidence Radiolabeled DG transacylation with inhibitor control; Co-IP and nuclear fractionation; intestine-specific double KO

    PMID:30926171 PMID:31035700 PMID:31412256

    Open questions at the time
    • Physiological significance of transacylase activity under normal HSL unclear
    • Nuclear degradation pathway from single lab
  15. 2021 Medium

    Connected ATGL lipolysis to glucose handling by showing it promotes TXNIP degradation to enhance GLUT1-mediated glucose uptake, expanding its role beyond fatty-acid metabolism.

    Evidence Knockdown/overexpression, TXNIP stability and GLUT1 surface assays in mouse and human adipocytes

    PMID:33508319

    Open questions at the time
    • Signal linking lipolysis to TXNIP turnover not fully defined
    • Single-lab mechanism
  16. 2022 High

    Established ATGL as the principal biosynthetic enzyme for FAHFAs via transacylation, identifying a signaling-lipid output of the lipase.

    Evidence Recombinant ATGL in vitro transacylation, catalytic-dead mutant, atglistatin, adipose-specific KO, validated in human tissue

    PMID:35676490

    Open questions at the time
    • Regulation of hydrolase-versus-transacylase partitioning unclear
    • Acceptor/donor specificity in vivo not fully mapped
  17. 2024 High

    Identified S-acylation at Cys15 by zDHHC11 as essential for catalysis and a Golgi PtdIns4P/CUL7FBXW8 glucose-sensing ubiquitylation circuit, plus a PNPLA3(148M) mechanism that sequesters ABHD5, defining post-translational and competitive controls on lipolysis.

    Evidence C15 mutagenesis with acylation/lipolysis assays; PtdIns4P/CUL7FBXW8 assembly and ubiquitylation assays with human liver; NanoBiT and purified-protein hydrolysis with Atgl-KO mice

    PMID:38561547 PMID:39143266 PMID:39550037

    Open questions at the time
    • How Cys15 acylation alters the catalytic mechanism not structurally defined
    • Interplay among competing ubiquitin ligases not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • An integrated structural and quantitative model of how the multiple competing co-activators, inhibitors, and post-translational modifications set ATGL output in each tissue remains unresolved.
  • No experimental high-resolution structure of full-length ATGL or its regulatory complexes
  • Relative in vivo weighting of CGI-58, G0S2, perilipin1, FSP27, acylation, and degradation not quantified
  • Determinants of hydrolase-versus-transacylase activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0016740 transferase activity 2
Localization
GO:0005811 lipid droplet 5 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4
Partners
ABHD5CIDECG0S2GBF1PLIN1PNPLA3STX11UBXD8

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Desnutrin/PNPLA2 encodes a 486-amino acid protein containing a patatin-like domain; ectopic overexpression in transfected cells increases triglyceride hydrolysis, establishing its lipase function. The fusion protein localizes to the cytoplasm as shown by confocal microscopy of EGFP-tagged desnutrin. Transfection/overexpression, triglyceride hydrolysis assay, confocal microscopy of EGFP-tagged protein The Journal of biological chemistry High 15337759
2006 Loss-of-function mutations in PNPLA2 (truncations affecting the hydrophobic domain but sparing the patatin active site) cause neutral lipid storage disease with myopathy (NLSDM), with triglyceride accumulation mimicked by siRNA knockdown of ATGL, establishing PNPLA2 as the rate-limiting triglyceride hydrolase in multiple tissues. Patient mutation analysis, siRNA knockdown with lipid accumulation readout Nature genetics High 17187067
2011 ATGL-catalyzed lipolysis of cellular triglycerides generates lipid ligands required for PPAR-α and PPAR-δ activation; in the heart, ATGL deficiency decreases PGC-1α/β expression, disrupts mitochondrial substrate oxidation and respiration, causing cardiomyopathy that is fully reversed by pharmacological PPAR-α agonist treatment. Atgl-knockout mouse model, mitochondrial respiration assays, PPAR-α agonist rescue, gene expression analysis Nature medicine High 21857651
2011 AMPK phosphorylates desnutrin/ATGL at serine 406, increasing its triacylglycerol hydrolase activity. Adipose-specific ATGL ablation converts brown adipose tissue to a WAT-like tissue with impaired thermogenesis and reduced UCP-1/PPARα signaling. Phosphorylation site mutagenesis, kinase assay, adipose-specific knockout mouse, thermogenesis assay, gene expression Cell metabolism High 21641555
2011 The minimal catalytically active domain of ATGL extends to leucine 254 (beyond the canonical patatin domain, Ile10–Leu178). This minimal fragment retains triacylglycerol hydrolase activity and can be co-activated by CGI-58 and inhibited by G0S2, and is sufficient for protein–protein interactions with both regulators. A 3D homology model of the minimal domain was generated. Domain truncation/mutagenesis, in vitro lipase activity assay, protein–protein interaction, homology modeling PloS one High 22039468
2010 UBXD8 directly binds ATGL on lipid droplets and promotes dissociation of the ATGL co-activator CGI-58, thereby inhibiting ATGL-mediated triacylglycerol hydrolysis and increasing lipid droplet size. UBXD8 recruits p97/VCP to lipid droplets through this interaction. Co-immunoprecipitation, direct binding assay, LD size measurement, overexpression/knockdown of UBXD8 Proceedings of the National Academy of Sciences of the United States of America High 23297223
2010 G0S2 inhibits ATGL activity and ATGL-mediated lipid droplet degradation. G0S2 binds ATGL independently of its activity state or the presence of CGI-58. CGI-58 co-activation cannot overcome G0S2-mediated inhibition, indicating non-competing regulatory mechanisms. Co-immunoprecipitation, lipid droplet morphology assay, overexpression studies Cell cycle (Georgetown, Tex.) Medium 20676045
2010 The C-terminal hydrophobic domain of ATGL is required for lipid droplet targeting and CGI-58-independent LD degradation. A deletion mutant lacking this domain fails to localize to LDs and cannot affect their morphology, though CGI-58 co-expression partially rescues this. Domain deletion mutagenesis, fluorescence localization, lipid droplet morphology assay Cell cycle (Georgetown, Tex.) Medium 20676045
2009 FoxO1 directly binds to two FoxO1-binding sites in the ATGL promoter and transcriptionally activates ATGL expression. Insulin controls nucleo-cytoplasmic shuttling of FoxO1 and regulates its interaction with the endogenous ATGL promoter in adipocytes. FoxO1 knockdown decreases ATGL expression and attenuates lipolysis. Luciferase reporter assay, ChIP, siRNA knockdown, lipolysis assay The Journal of biological chemistry High 19297333
2006 Insulin downregulates ATGL mRNA via PI3-kinase and p70 S6 kinase pathways. TNF-α downregulates ATGL in parallel with PPARγ reduction, effects attenuated by MEK, PI3K, and mTOR inhibitors. PPARγ transcriptionally activates the ATGL promoter (identified through 5'-flanking region luciferase reporter deletion analysis). Luciferase reporter assay with promoter deletions, pharmacological inhibitors, adipocyte cell culture American journal of physiology. Endocrinology and metabolism Medium 16705060
2013 Insulin inhibits ATGL transcription through an evolutionarily conserved mTORC1–Egr1 pathway. Egr1 directly inhibits the ATGL promoter in vitro and in cultured adipocytes. The pathway was identified by genetic screen in yeast (Msn4p/Tor1 axis as ATGL ortholog regulator) and validated in mammalian cells. Yeast genetic screen, Egr1 promoter binding assay, adipocyte knockdown/overexpression, high-fat-diet mouse model Molecular and cellular biology High 23858058
2011 SIRT1 controls ATGL transcription by deacetylating FoxO1, thereby regulating FoxO1's functional activity at the ATGL promoter. SIRT1 knockdown decreases ATGL expression and attenuates lipolysis in adipocytes. shRNA knockdown, lipolysis assay, dominant-negative AMPK cell line, gene expression analysis Journal of lipid research Medium 21743036
2015 ATGL-catalyzed lipolysis positively regulates SIRT1 deacetylase activity to promote PGC-1α signaling and oxidative metabolism, independent of changes in NAD+. ATGL mediates β-adrenergic signaling effects on SIRT1 activity and PPAR-α target gene expression, establishing SIRT1 as a critical node linking lipolysis to transcriptional regulation of oxidative metabolism. ATGL overexpression/knockdown, SIRT1 deacetylase activity assay, gene expression, β-adrenergic stimulation Diabetes Medium 25614670
2013 Desnutrin/ATGL ablation in pancreatic β-cells impairs glucose-stimulated insulin secretion (GSIS) by reducing lipolysis-derived PPARδ ligands, which are required for normal mitochondrial oxidative gene expression and ATP production. Synthetic PPARδ (but not PPARα) agonist restores GSIS in β-cell-specific KO mice. β-cell-specific Atgl KO, GSIS assay, mitochondrial respiration, PPARδ agonist rescue, adenoviral ATGL re-expression Cell metabolism High 24268737
2014 FSP27 (amino acids 120–220) directly interacts with ATGL to inhibit its lipolytic function and promote triglyceride storage in human adipocytes. FSP27 depletion increases lipolysis and inhibits insulin signaling via reduced AKT phosphorylation, which is rescued by ATGL depletion or exogenous FSP27 expression. Co-immunoprecipitation, domain mapping, siRNA knockdown, lipolysis assay, insulin signaling assay in human adipocytes The Journal of biological chemistry High 24627478
2011 GBF1 (Golgi Brefeldin A resistance factor 1) and ATGL interact directly; multiple contact sites exist: the C-terminal region of ATGL interacts with N-terminal (including Sec7) domains of GBF1, while the patatin (lipase) domain of ATGL interacts with GBF1 HDS1 and HDS2 C-terminal domains. This interaction contributes to ATGL delivery to lipid droplets via a GBF1/Arf1/COPI trafficking pathway. Yeast two-hybrid, co-immunoprecipitation, direct protein binding, subcellular localization of GBF1 domain fragments PloS one Medium 21789191
2012 Perilipin 1, but not FSP27, directly inhibits ATGL triacylglycerol hydrolase activity in vitro and attenuates CGI-58-dependent co-activation of ATGL. Perilipin 1 is required for isoproterenol-stimulated translocation of ATGL to lipid droplets, while FSP27 constitutively limits LD presence of ATGL. In vitro triacylglycerol hydrolase assay, siRNA knockdown, overexpression, LD translocation imaging Molecular endocrinology (Baltimore, Md.) High 23204327
2013 In skeletal muscle, contraction stimulation increases the ATGL–CGI-58 interaction by 128%. ATGL interacts with PLIN2, PLIN3, and PLIN5 at rest; the PLIN2–ATGL interaction decreases 21% with contraction. PLIN2 does not interact with CGI-58, suggesting PLINs differentially regulate ATGL–CGI-58 association. Co-immunoprecipitation from rat skeletal muscle at rest vs. electrically stimulated contraction American journal of physiology. Regulatory, integrative and comparative physiology Medium 23408028
2016 In vivo, adipose-specific knockout of both AMPK α1 and α2 subunits abolishes phosphorylation of desnutrin/ATGL at S406, reducing triacylglycerol hydrolase activity and lowering basal lipolysis, providing direct in vivo evidence that AMPK phosphorylates and activates ATGL. AMPK-ASKO mice also show defective HSL phosphorylation at S565. Adipose-specific AMPK double-knockout mouse, phosphorylation analysis, TAG hydrolase activity assay, adipocyte lipolysis assay Molecular and cellular biology High 27185873
2022 ATGL catalyzes FAHFA (fatty acid esters of hydroxy fatty acids) biosynthesis via a transacylation reaction, esterifying a hydroxy fatty acid with a fatty acid from triglyceride or diglyceride. Catalytically dead ATGL fails to increase FAHFA production; chemical inhibition or genetic deletion of Atgl reduces FAHFA and FAHFA-TG levels by 80–90% in adipose tissue. ATGL transacylase activity is present in human adipose tissue. Recombinant ATGL in vitro transacylation assay, catalytic dead mutant, chemical inhibition (atglistatin), adipose-specific Atgl KO mouse, chemical biology/proteomics Nature High 35676490
2024 zDHHC11 S-acylates ATGL at cysteine 15, and this modification is required for ATGL catalytic activity. Preventing S-acylation (C15 mutation) renders ATGL catalytically inactive despite proper lipid droplet localization, causing LD accumulation and defective lipolysis/lipophagy. Overexpression of zDHHC11 reduces LD size; its elimination enlarges LDs. Site-directed mutagenesis (C15), S-acylation assay, lipolysis assay, LD imaging, overexpression/knockdown in hepatocytes and mice Nature metabolism High 39143266
2024 PNPLA3(148M) promotes hepatic steatosis as a gain-of-function by accumulating on lipid droplets and sequestering ABHD5 (CGI-58) away from ATGL, thereby limiting ATGL-mediated TG hydrolysis. ABHD5 activates both PNPLA3 and ATGL in vitro. PNPLA3(148M)-associated inhibition of TG hydrolysis requires ATGL expression and LD localization of PNPLA3. Overexpression of ABHD5 reversed hepatic steatosis in Pnpla3M/M mice. NanoBiT complementation assay, in vitro TG hydrolysis with purified recombinant proteins, liver-specific Atgl-KO mice, adenoviral/AAV expression, immunocytochemistry Journal of hepatology High 39550037
2024 Intracellular glucose depletion lowers Golgi PtdIns4P levels, reducing assembly of the CUL7FBXW8 E3 ubiquitin ligase complex in the Golgi, which decreases polyubiquitylation of ATGL and enhances ATGL-driven lipolysis. This constitutes a cell-intrinsic glucose-sensing mechanism controlling FA liberation from lipid droplets. PtdIns4P manipulation, CUL7FBXW8 assembly assay, ATGL ubiquitylation assay, genetic/pharmacological manipulation in mouse models and ex vivo human liver perfusion Nature cell biology High 38561547
2019 PEDF promotes proteasomal degradation of ATGL via COP1-mediated polyubiquitylation. PEDF enhances nuclear import of ATGL for its subsequent proteasomal degradation in the nucleus. This COP1–ATGL axis controls hepatocyte lipid accumulation and mobilization. Co-immunoprecipitation, proteasome inhibitor assay, nuclear fractionation, overexpression/knockdown of COP1 and PEDF in hepatocytes Biochemical and biophysical research communications Medium 30926171
2017 LDAH (lipid droplet-associated hydrolase) enhances polyubiquitination and proteasomal degradation of ATGL, thereby increasing TAG levels and LD size. Co-expression of ATGL reverses the LD phenotype induced by LDAH overexpression. Ubiquitination assay, pulse-chase, overexpression/knockdown in HEK293 cells, TAG measurement, LD morphology Scientific reports Medium 28578400
2016 G0S2 protein stability is regulated by K48-linked polyubiquitination at lysine 25; mutation of K25 abolishes ubiquitination and stabilizes G0S2. ATGL expression stabilizes G0S2 protein (but not mRNA); G0S2 protein levels are reduced in adipose tissue of ATGL-deficient mice, confirming ATGL's role in G0S2 stabilization. Ubiquitination assay, site-directed mutagenesis (K25), Atgl-KO mouse tissue analysis, protein stability assay PloS one Medium 27248498
2008 ATGL protein is expressed in human skeletal muscle exclusively in type I (oxidative) muscle fibers, as established by immunohistochemistry and immunofluorescence with fiber-type markers. Immunohistochemistry, immunofluorescence, fiber-type co-staining in human vastus lateralis biopsies Histochemistry and cell biology Medium 18224330
2014 Hepatic ATGL channels hydrolyzed fatty acids preferentially to β-oxidation and induces PPAR-α signaling independent of liver fatty acid binding protein (L-FABP). L-FABP deletion does not impair ATGL-mediated FA channeling to mitochondria or PPAR-α target gene regulation. Adenovirus-mediated ATGL knockdown/overexpression in WT and L-FABP KO mice, primary hepatocyte oxidation assays, serum β-hydroxybutyrate measurement Journal of lipid research Medium 24610891
2020 ATGL cooperates with ABHD5/CGI-58 to mobilize lipids from lipid droplets for hepatitis C virus assembly and lipoprotein morphogenesis. ABHD5 residues critical for ATGL activation, when grafted onto the non-activating paralog ABHD4, restored both pro-viral and lipolytic functions, defining the ABHD5–ATGL protein interface required for co-lipase activity. ATGL expression modulation, chemical inhibition (atglistatin), ABHD5 chimeric protein engineering, co-immunoprecipitation, lipid droplet lipolysis assay, viral production assay PLoS pathogens High 32542055
2022 STX11 directly binds ATGL via its C-terminal domain interacting with the patatin domain-containing segment of ATGL, preventing ATGL translocation to lipid droplets by recruiting ATGL to the ER. STX11 deficiency in hepatocytes promotes lipolysis via ATGL-SIRT1 signaling and enhances lipophagy. Co-immunoprecipitation, domain mapping, subcellular localization imaging, overexpression/knockdown, lipid hydrolysis assay iScience Medium 35372814
2019 In the intestine, ATGL/CGI-58 specifically catalyzes hydrolysis of a lipid storage pool derived from basolateral (blood-side) lipid uptake/secretion–re-uptake cycle, but is not involved in providing substrates for chylomicron synthesis from dietary lipids. Intestine-specific ATGL/CGI-58 double KO mice, dietary lipid challenge, lipid droplet accumulation analysis Cell reports Medium 31412256
2014 HCV core protein localizes to lipid droplet surfaces and inhibits ATGL-mediated lipolysis without directly interacting with ATGL or CGI-58, but unexpectedly increases ATGL–CGI-58 interaction and recruitment of both to LDs. ATGL-KO MEFs expressing core show no decrease in TG degradation, confirming core acts through ATGL. Co-immunoprecipitation, ATGL-KO mouse embryonic fibroblasts, ex vivo LD TG hydrolysis assay The Journal of biological chemistry Medium 25381252
2017 Combined adipose-specific deficiency of ATGL and HSL (DAKO mice) causes fully penetrant liposarcoma in all mice by 11–14 months, establishing a genetic epistatic interaction between Pnpla2 and Lipe; this phenotype does not occur with either single knockout alone. Double adipose-specific KO mouse (epistasis), tumor histology, transcriptome analysis PLoS genetics High 28459858
2019 When HSL is deficient, ATGL functions as a transacylase, transferring an acyl group from one diacylglycerol to another, forming a triglyceride plus a monoglyceride. This ATGL transacylase activity was abolished by a specific ATGL inhibitor, revealing a previously unknown physiological redundancy between ATGL and HSL. Radiolabeled DG incubation with HSL-deficient lipid droplet fractions, ATGL-specific inhibitor (atglistatin) treatment Cells Medium 31035700
2016 ATGL overexpression in ATGL-deficient hepatocellular carcinoma cells activates PPAR-α/p300-mediated acetylation and accumulation of p53 protein (without altering p53 mRNA), rewiring metabolism toward oxidative fatty acid metabolism and reducing glucose uptake/glycolysis. ATGL overexpression in HCC cell lines, p53 knockdown/KO epistasis, PPAR-α/p300 inhibition, metabolic assays Oncogene Medium 30367149
2021 ATGL-mediated lipolysis regulates glucose uptake in adipocytes via TXNIP stability: cAMP-induced ATGL activation promotes TXNIP degradation, selectively inducing GLUT1 surface localization and glucose uptake. ATGL knockdown prevents cAMP-dependent TXNIP degradation and reduces glucose uptake; this mechanism was validated in human primary adipocytes. siRNA knockdown, ATGL overexpression, TXNIP stability assay, GLUT1 surface localization, glucose uptake assay in 3T3-L1 and human primary adipocytes The Journal of biological chemistry Medium 33508319
2016 ATGL and CGI-58 are co-resident on lipid droplets in rat hepatic stellate cells (HSC-T6). Rat ATGL co-activated by rat CGI-58 efficiently hydrolyzes both triacylglycerols and retinyl esters in vitro. LD proteomics, LD isolation, in vitro hydrolase activity assay with rATGL and rCGI-58 Journal of lipid research Medium 26330055

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 649 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 383 17187067
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
2016 AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue. Molecular and cellular biology 228 27185873
2010 Dysregulation of lipolysis and lipid metabolism in visceral and subcutaneous adipocytes by high-fat diet: role of ATGL, HSL, and AMPK. American journal of physiology. Cell physiology 219 20107043
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 195 23297223
2009 FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. The Journal of biological chemistry 188 19297333
2018 Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation. Molecular cancer 175 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
2015 ATGL-catalyzed lipolysis regulates SIRT1 to control PGC-1α/PPAR-α signaling. Diabetes 165 25614670
2008 Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. Journal of lipid research 164 19050316
2011 SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. Journal of lipid research 155 21743036
2018 Of mice and men: The physiological role of adipose triglyceride lipase (ATGL). Biochimica et biophysica acta. Molecular and cell biology of lipids 141 30367950
2013 Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Molecular and cellular biology 132 23858058
2022 ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature 103 35676490
2013 Desnutrin/ATGL activates PPARδ to promote mitochondrial function for insulin secretion in islet β cells. Cell metabolism 103 24268737
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
2012 Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) deficiencies affect expression of lipolytic activities in mouse adipose tissues. Molecular & cellular proteomics : MCP 97 22984285
2010 Differential control of ATGL-mediated lipid droplet degradation by CGI-58 and G0S2. Cell cycle (Georgetown, Tex.) 97 20676045
2016 LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL). Scientific reports 96 27759039
2022 ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. Cell reports 86 35675775
2012 Fasting energy homeostasis in mice with adipose deficiency of desnutrin/adipose triglyceride lipase. Endocrinology 86 22374972
2011 The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene. Journal of neurology 82 21544567
2011 The minimal domain of adipose triglyceride lipase (ATGL) ranges until leucine 254 and can be activated and inhibited by CGI-58 and G0S2, respectively. PloS one 77 22039468
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 The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes. Diabetes 76 16644682
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 71 29472527
2014 Lipid droplet protein LID-1 mediates ATGL-1-dependent lipolysis during fasting in Caenorhabditis elegans. Molecular and cellular biology 70 25202121
2012 Fenofibrate lowers lipid accumulation in myotubes by modulating the PPARα/AMPK/FoxO1/ATGL pathway. Biochemical pharmacology 63 22687626
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 60 32729974
2016 ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2. Autophagy 58 27559856
2018 Coordination Among Lipid Droplets, Peroxisomes, and Mitochondria Regulates Energy Expenditure Through the CIDE-ATGL-PPARα Pathway in Adipocytes. Diabetes 57 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 52 24836204
2018 Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53. Oncogene 48 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
2024 PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. Journal of hepatology 46 39550037
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
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 40 25956450
2009 Chronic TNFalpha and cAMP pre-treatment of human adipocytes alter HSL, ATGL and perilipin to regulate basal and stimulated lipolysis. FEBS letters 40 19695247
2014 Hepatic ATGL mediates PPAR-α signaling and fatty acid channeling through an L-FABP independent mechanism. Journal of lipid research 39 24610891
2020 The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly. PLoS pathogens 38 32542055
2016 ATGL and DGAT1 are involved in the turnover of newly synthesized triacylglycerols in hepatic stellate cells. Journal of lipid research 38 27179362
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
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
2009 Regulation of ATGL expression mediated by leptin in vitro in porcine adipocyte lipolysis. Molecular and cellular biochemistry 34 19626423
2016 PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 27485820
2015 PEDF and PEDF-derived peptide 44mer stimulate cardiac triglyceride degradation via ATGL. Journal of translational medicine 33 25890298
2019 Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy. JCI insight 32 31185001
2012 Fat-reducing effects of dehydroepiandrosterone involve upregulation of ATGL and HSL expression, and stimulation of lipolysis in adipose tissue. Steroids 31 22951290
2019 ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans. Molecular metabolism 30 31311719
2019 ATGL/CGI-58-Dependent Hydrolysis of a Lipid Storage Pool in Murine Enterocytes. Cell reports 29 31412256
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
2024 Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL. Nature cell biology 28 38561547
2024 S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes. Nature metabolism 28 39143266
2024 Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. Journal of hepatology 28 39357546
2021 Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity. Oncogenesis 28 34845203
2014 The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. The Journal of biological chemistry 28 25381252
2015 A myopathy with unusual features caused by PNPLA2 gene mutations. Muscle & nerve 26 25287355
2012 Higher levels of ATGL are associated with exercise-induced enhancement of lipolysis in rat epididymal adipocytes. PloS one 26 22815850
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 25 39748508
2024 Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides. Brain, behavior, and immunity 25 39326768
2023 Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis. Cell death & disease 25 36746922
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 4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL. The Journal of biological chemistry 25 25814662
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
2022 Recent Advances on the Role of ATGL in Cancer. Frontiers in oncology 24 35912266
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 24 32454271
2017 Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma. Anticancer research 24 28179319
2022 The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy. iScience 23 35372814
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 Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation. Scientific reports 23 28578400
2021 Palmitate induces fat accumulation via repressing FoxO1-mediated ATGL-dependent lipolysis in HepG2 hepatocytes. PloS one 22 33449950
2011 ATGL and HSL are not coordinately regulated in response to fuel partitioning in fasted rats. The Journal of nutritional biochemistry 22 20621463
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
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
2023 BETi enhance ATGL expression and its lipase activity to exert their antitumoral effects in triple-negative breast cancer (TNBC) cells. Journal of experimental & clinical cancer research : CR 19 36604676
2021 ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes. The Journal of biological chemistry 19 33508319
2017 Atgl gene deletion predisposes to proximal tubule damage by impairing the fatty acid metabolism. Biochemical and biophysical research communications 19 28400046
2013 PNPLA2 mutation: a paediatric case with early onset but indolent course. Neuromuscular disorders : NMD 19 24074500
2019 PEDF promotes nuclear degradation of ATGL through COP1. Biochemical and biophysical research communications 18 30926171
2016 Regulation of G0/G1 Switch Gene 2 (G0S2) Protein Ubiquitination and Stability by Triglyceride Accumulation and ATGL Interaction. PloS one 18 27248498
2012 A novel mutation in PNPLA2 leading to neutral lipid storage disease with myopathy. Archives of neurology 18 22964912
2011 Metformin regulates hepatic lipid metabolism through activating AMP-activated protein kinase and inducing ATGL in laying hens. European journal of pharmacology 18 21958877
2021 Resting skeletal muscle PNPLA2 (ATGL) and CPT1B are associated with peak fat oxidation rates in men and women but do not explain observed sex differences. Experimental physiology 17 33675111
2020 Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection. Autophagy 17 32777979
2008 cDNA cloning, characterization, and variation analysis of chicken adipose triglyceride lipase (ATGL) gene. Molecular and cellular biochemistry 16 18679582

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