Affinage

PNPLA3

1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 · UniProt Q9NST1

Length
481 aa
Mass
52.9 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PNPLA3 is a lipid droplet-associated lipase whose primary pathophysiological role centers on regulation of hepatic triglyceride turnover through its interaction with the ATGL co-activator ABHD5/CGI-58. The enzyme possesses intrinsic triglyceride hydrolase activity dependent on catalytic Ser-47, and also mediates transfer of polyunsaturated fatty acids from triglycerides to phosphatidylcholine; its expression is transcriptionally driven by SREBP-1c (binding intron 1 and a promoter SRE) and insulin/glucose signaling, and further regulated by ER-α through a gene-intrinsic enhancer, while its protein turnover is controlled by BFAR-mediated ubiquitylation and stabilized by fatty acids (PMID:16150821, PMID:20385813, PMID:25655569, PMID:37749332, PMID:38294943, PMID:39054606). The common I148M variant escapes ubiquitin-mediated degradation, accumulates on hepatic lipid droplets—including at aberrant lipid droplet–Golgi contact sites—and sequesters ABHD5 away from ATGL in a gain-of-function manner that is both necessary and sufficient for hepatic steatosis, as demonstrated by genetic epistasis with Cgi-58 knockout, ASO-mediated silencing, and PROTAC-directed degradation in knockin mice (PMID:24917523, PMID:31019090, PMID:30802989, PMID:39550037, PMID:30772256, PMID:38657050). In hepatic stellate cells, I148M additionally impairs LXRα signaling, mitochondrial complex IV function, and NR4A1-mediated TGF-β inhibition, activating Yap/Hedgehog pathways to promote fibrogenesis (PMID:31497741, PMID:33218077, PMID:38365182).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 Medium

    Identifying PNPLA3 as a nutritionally regulated, membrane-associated adipocyte gene established the first link between this gene and metabolic energy sensing, raising the question of its enzymatic function.

    Evidence mRNA differential display during 3T3-L1 differentiation; Western blot and confocal microscopy of epitope-tagged protein

    PMID:11431482

    Open questions at the time
    • Enzymatic activity unknown
    • Hepatic expression not yet examined
    • Subcellular localization based on overexpression, not endogenous protein
  2. 2005 High

    Demonstrating that PNPLA3 has Ser-47-dependent triglyceride hydrolase activity in vitro—yet does not reduce cellular triglycerides upon overexpression—posed the central paradox of why a lipase does not promote net lipolysis.

    Evidence In vitro lipase assay with active-site serine mutants; intracellular TG measurement after overexpression

    PMID:16150821

    Open questions at the time
    • Physiological substrate specificity undefined
    • No in vivo loss-of-function data
    • Role in hepatocytes not tested
  3. 2006 High

    siRNA knockdown showing no effect on adipocyte lipolysis, combined with opposite regulation by insulin relative to ATGL, indicated that PNPLA3 is not a conventional lipolytic enzyme and hinted at a distinct, possibly anabolic or regulatory, function.

    Evidence siRNA knockdown in 3T3-L1 adipocytes; glycerol/NEFA release assays; insulin dose–response

    PMID:16380488 PMID:16914601

    Open questions at the time
    • Hepatocyte function unknown
    • Mechanism of insulin-mediated transcriptional induction not dissected
    • Protein-level regulation not addressed
  4. 2010 High

    Two advances resolved the transcriptional and post-translational control of PNPLA3: SREBP-1c was shown to directly drive transcription via an intron 1 element (explaining carbohydrate/LXR-agonist induction), and fatty acids were found to stabilize the protein, together creating a feed-forward loop; concurrently, global Pnpla3 knockout mice showed no metabolic phenotype, ruling out a simple loss-of-function mechanism for disease.

    Evidence ChIP and EMSA for SREBP-1c binding; pulse-chase half-life measurement in HuH-7 cells; Pnpla3−/− mice on multiple diets

    PMID:20385813 PMID:20648554 PMID:21068004

    Open questions at the time
    • How I148M variant causes steatosis still unknown
    • E3 ligase for PNPLA3 degradation unidentified
    • LD targeting mechanism not characterized
  5. 2014 High

    Knockin mice carrying I148M or the catalytic-dead S47A showed that protein accumulation on lipid droplets—rather than aberrant enzymatic gain—drives steatosis, fundamentally reframing I148M as a gain-of-function through protein stability.

    Evidence CRISPR/knockin mice (I148M, S47A); LD fractionation; hepatic lipid quantification on high-sucrose diet

    PMID:24917523

    Open questions at the time
    • Mechanism by which LD-accumulated PNPLA3 causes TG accumulation unknown
    • Protein interaction partners on LDs not identified
    • Ubiquitylation pathway not characterized
  6. 2015 High

    Dissection of the human PNPLA3 promoter revealed a proximal SRE at −97/−88 bp bound by SREBP-1c and synergistic NFY binding, with insulin acting through PI3K, completing the transcriptional regulatory map.

    Evidence Luciferase reporters with promoter deletion/mutation; EMSA; PI3K inhibitor treatment in HepG2 cells

    PMID:25655569

    Open questions at the time
    • Chromatin context of PNPLA3 regulation not fully explored
    • Enhancer elements beyond the proximal promoter not examined
  7. 2019 High

    Three convergent studies established the core disease mechanism: (1) ubiquitylation-resistant PNPLA3-WT on LDs phenocopies steatosis, proving accumulation alone is sufficient; (2) PNPLA3 directly binds ABHD5/CGI-58, and its pro-steatotic effect requires CGI-58 (genetic epistasis in Cgi-58 KO mice); (3) ASO-mediated silencing of Pnpla3-148M reverses steatosis, inflammation, and fibrosis in knockin mice.

    Evidence Ubiquitylation-resistant construct + shRNA + PROTAC in mice; co-IP with purified proteins + Cgi-58 liver KO epistasis; GalNAc3-ASO in 148M/M knockin mice on NASH diets

    PMID:30772256 PMID:30802989 PMID:31019090

    Open questions at the time
    • E3 ligase identity still unknown
    • Structural basis of PNPLA3–ABHD5 interaction not resolved
    • Whether ABHD5 activates or is merely sequestered by PNPLA3 debated
  8. 2019 Medium

    In hepatic stellate cells, I148M was shown to impair LXRα transcriptional activity and cholesterol efflux, identifying a cell-type-specific fibrogenic mechanism independent of hepatocyte TG accumulation.

    Evidence Primary human HSCs and LX-2 cells; LXR response-element luciferase assays; cholesterol quantification; LXR agonist rescue

    PMID:31497741

    Open questions at the time
    • Direct PNPLA3–LXRα interaction not demonstrated
    • In vivo HSC-specific validation lacking
    • Whether cholesterol dysregulation is cause or consequence of fibrogenesis unclear
  9. 2020 Medium

    I148M in HSCs was found to enhance Yap/Hedgehog signaling and shift metabolism toward anaerobic glycolysis upon TGF-β stimulation, linking the variant to pro-fibrogenic signaling cascades.

    Evidence PNPLA3-I148M overexpression in LX-2 HSCs; Yap reporter; AMPK phosphorylation and lactate assays; Verteporfin inhibition

    PMID:33218077

    Open questions at the time
    • Overexpression system may not reflect endogenous levels
    • Direct molecular link between PNPLA3 and Yap activation unknown
    • No in vivo validation
  10. 2023 High

    Identification of an ER-α-bound enhancer within PNPLA3 whose deletion abolishes I148M-driven lipid accumulation and fibrogenesis added a hormonal layer to PNPLA3 transcriptional control and suggested a mechanism for sex-specific disease risk.

    Evidence ChIP for ER-α; luciferase assays; CRISPR deletion of enhancer in 3D multilineage liver spheroids

    PMID:37749332

    Open questions at the time
    • In vivo validation of ER-α enhancer deletion not performed
    • Interaction with SREBP-1c-driven regulation not integrated
    • Sex-specific phenotype in animal models not tested
  11. 2024 High

    Four studies in 2024 resolved major remaining questions: BFAR was identified as the E3 ubiquitin ligase for PNPLA3 (explaining I148M resistance to degradation); endogenous PNPLA3/I148M was localized to LDs, Golgi, and endosomes with I148M inducing aberrant LD–Golgi contacts; ABHD5 was shown to activate (not merely be sequestered by) PNPLA3; and TM6SF2-E167K was found to enhance PNPLA3 interaction, impairing PUFA transfer from TG to PC.

    Evidence In vitro ubiquitylation reconstitution + Bfar KO mice; isogenic CRISPR hepatoma lines with fractionation and phosphoinositide binding; NanoBiT assay + in vitro TG hydrolysis ± ABHD5 + genetic epistasis in Atgl−/− mice; Tm6sf2-167K knockin mice with lipidomics and co-IP

    PMID:38294943 PMID:38657050 PMID:39054606 PMID:39550037

    Open questions at the time
    • Structural basis of BFAR–PNPLA3 recognition not resolved
    • Whether I148M specifically evades BFAR or any E3 not determined
    • Functional significance of Golgi and endosomal pools of PNPLA3 unclear
  12. 2024 Medium

    In HSCs, I148M was linked to mitochondrial complex IV insufficiency, increased ROS, and suppression of NR4A1, an endogenous TGF-β1 inhibitor, providing a mechanistic basis for the variant's pro-fibrogenic action in stellate cells.

    Evidence RNA-seq of primary human HSCs and liver biopsies; 3D ECM scaffold cultures; mitochondrial complex assays; NR4A1 agonist rescue

    PMID:38365182

    Open questions at the time
    • Causal chain from PNPLA3-I148M to complex IV deficiency not established
    • Single-lab finding without independent replication
    • Whether mitochondrial defect is direct or secondary to cholesterol/lipid changes unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of PNPLA3–ABHD5 and PNPLA3–BFAR interactions, why I148M specifically resists BFAR-mediated ubiquitylation, the physiological role of PNPLA3 at the Golgi and endosomes, and whether HSC-specific mechanisms (LXR, Yap, mitochondrial dysfunction) operate through a shared upstream lipid intermediate or independent pathways.
  • No crystal or cryo-EM structure of PNPLA3 or its complexes
  • BFAR recognition determinants on PNPLA3 and how I148M escapes ubiquitylation not defined
  • Golgi/endosomal function of PNPLA3 mechanistically uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0008289 lipid binding 1 GO:0016740 transferase activity 1
Localization
GO:0005811 lipid droplet 6 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 1
Partners
ABHD5BFARESR1NFYSREBF1TM6SF2

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Adiponutrin (PNPLA3) is an adipose-specific transmembrane protein localized to membranes (not cytosol), identified by mRNA differential display during adipocyte differentiation; its mRNA is dramatically regulated by nutritional state (virtually absent during fasting, strongly induced by high-carbohydrate refeeding). mRNA differential display, Western blot, confocal microscopy with epitope-tagged protein in 3T3-L1 adipocytes and COS cells The Journal of biological chemistry Medium 11431482
2005 PNPLA3 (adiponutrin) has in vitro triglyceride hydrolase (lipase) activity that depends on the active-site serine; however, unlike ATGL/desnutrin, overexpression of adiponutrin does not decrease intracellular triglyceride levels, suggesting its in vitro lipase activity does not translate to net lipolysis in cells. In vitro lipase activity assay with active-site serine mutants; overexpression in cells with intracellular TG measurement Journal of lipid research High 16150821
2006 siRNA-mediated knockdown of adiponutrin (PNPLA3) in 3T3-L1 adipocytes has no effect on basal or stimulated glycerol or NEFA release, indicating that PNPLA3 does not contribute to net adipocyte lipolysis; PNPLA3 expression is oppositely regulated by insulin compared to ATGL (insulin increases PNPLA3, decreases ATGL). siRNA knockdown in 3T3-L1 adipocytes; glycerol/NEFA release assay; dose- and time-dependent insulin treatment Diabetes High 16380488
2006 Adiponutrin (PNPLA3) mRNA in human adipose tissue is induced ~8-fold by insulin infusion and ~2-fold by glucose infusion, with additive effects; the regulation is impaired in type-2 diabetics but maintained in type-1 diabetics with chronic hyperglycemia. Euglycemic hyperinsulinemic and hyperglycemic clamp studies in humans; RT-qPCR of subcutaneous adipose tissue European journal of endocrinology Medium 16914601
2010 PNPLA3 transcription is directly activated by SREBP-1c, which binds to intron 1 of Pnpla3; PNPLA3 mRNA increases ~90-fold with carbohydrate feeding (also mimicked by LXR agonist treatment); additionally, fatty acids (C16:0, C18:1, C18:2) stabilize PNPLA3 protein post-translationally by prolonging its half-life (from 2.4 to 6.7 h), creating a feed-forward loop. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), LXR agonist treatment, pulse-chase protein half-life measurement in HuH-7 hepatocytes Proceedings of the National Academy of Sciences of the United States of America High 20385813
2010 Global knockout of Pnpla3 in mice does not affect body weight, adipose mass, hepatic or plasma triglyceride content, liver enzymes, glucose tolerance, or insulin tolerance under multiple dietary challenges (chow, high-fat, high-sucrose, lipogenic diets, or ob/ob background), indicating that PNPLA3 loss-of-function does not cause fatty liver disease. Gene targeting (Pnpla3-/- mice); metabolic phenotyping under multiple diet conditions; liver histology and biochemistry Hepatology (Baltimore, Md.) High 20648554 21068004
2014 Knockin mice expressing the I148M variant of PNPLA3 at physiological levels develop hepatic steatosis on a high-sucrose diet, accompanied by a 40-fold accumulation of PNPLA3 protein on hepatic lipid droplets with no increase in mRNA; an enzymatically dead S47A catalytic mutant produces the same phenotype, indicating that catalytic inactivity and LD accumulation — rather than gain of enzymatic function — underlie steatosis. CRISPR/knockin mouse model (I148M and S47A); hepatic lipid quantification; immunoblotting of lipid droplet fractions; dietary challenge Hepatology (Baltimore, Md.) High 24917523
2015 SREBP-1c directly binds a sterol regulatory element (SRE) motif at -97 to -88 bp in the human PNPLA3 promoter; NFY binding at -26/-22 bp synergizes with SREBP-1c to transactivate PNPLA3; insulin activates this pathway via PI3K, increasing SREBP-1c binding to the PNPLA3 promoter. Luciferase reporter assays with promoter deletion/mutation constructs; gel-shift (EMSA); PI3K inhibitor (LY294002) treatment in HepG2 cells Journal of cellular physiology High 25655569
2019 Accumulation of catalytically inactive PNPLA3 on hepatic lipid droplets is causally sufficient for steatosis: a ubiquitylation-resistant form of PNPLA3-WT that accumulates on LDs (without loss of enzymatic activity) causes FLD in mice; shRNA knockdown or PROTAC-mediated degradation of PNPLA3(148M) reduces liver TG content, confirming that LD accumulation — not enzymatic defect per se — drives steatosis. Mouse liver expression of ubiquitylation-resistant PNPLA3 (AAV/adenovirus); shRNA knockdown; PROTAC degradation; hepatic TG quantification; LD fractionation Proceedings of the National Academy of Sciences of the United States of America High 31019090
2019 PNPLA3 interacts directly with CGI-58 (ABHD5), the cofactor of ATGL; overexpressed PNPLA3 (WT or 148M) inhibits ATGL-mediated lipid droplet depletion in HuH-7 cells; PNPLA3 fails to localize to hepatic LDs in liver-specific Cgi-58 KO mice; PNPLA3(148M) overexpression increases hepatic TG in WT but not Cgi-58 KO mice, establishing a CGI-58-dependent mechanism. Co-immunoprecipitation and pulldown with purified proteins; co-expression experiments in HuH-7 cells; liver-specific Cgi-58 KO mice; hepatic TG quantification Hepatology (Baltimore, Md.) High 30802989
2017 Alcohol (binge and chronic) increases PNPLA3 protein and mRNA in hepatocytes and liver through epigenetic mechanisms: chromatin immunoprecipitation (ChIP) shows increased association of acetylated histone H3K9 with the PNPLA3 gene promoter after ethanol exposure. ChIP assay with H3AcK9 antibody; in vitro rat hepatocytes + in vivo mouse and rat binge/chronic ethanol models; PNPLA3 protein and mRNA quantification Alcohol (Fayetteville, N.Y.) Medium 28433418
2019 The I148M variant in PNPLA3 expressed in human hepatic stellate cells (HSCs) reduces LXRα signaling and transcriptional activity, leading to impaired cholesterol efflux, decreased oxysterol-generating enzyme expression, and intracellular cholesterol accumulation; LXR agonist treatment restores LXR functionality and reduces fibrogenic gene expression in I148M HSCs. Primary human HSC isolation and genotyping; LX-2 overexpression; luciferase assays on LXR response element; gene expression by qPCR; cholesterol measurement Hepatology communications Medium 31497741
2020 In HSCs carrying PNPLA3 I148M, TGF-β upregulates PNPLA3 transcript and protein rapidly, and these cells show enhanced Yap and Hedgehog signaling, increased anaerobic glycolysis (higher lactate, decreased AMPK phosphorylation), and elevated Yap target gene expression; Yap inhibitor (Verteporfin) and PPARγ agonist (Rosiglitazone) abrogate these effects. PNPLA3 I148M overexpression in LX-2 HSCs; TGF-β/leptin treatment; Yap luciferase reporter assay; AMPK phosphorylation; lactate release; Verteporfin treatment International journal of molecular sciences Medium 33218077
2022 The PNPLA3 I148M variant causes elevated NF-κB and IL-6/STAT3 signaling in isogenic hPSC-derived multicellular liver cultures (hepatocytes + stellate cells + macrophages); dampening IL-6/STAT3 activity alleviates I148M-mediated NAFLD phenotypes, and an ER-α binding site within a PNPLA3 enhancer (identified by ChIP) drives I148M upregulation in hepatocytes. Isogenic hPSC-derived multicellular liver cultures; CRISPR-Cas9 genome editing of rs738409; IL-6/STAT3 pathway inhibition; NF-κB activity assays; transcriptomics Journal of hepatology Medium 36049612
2023 Estrogen receptor-α (ER-α) directly binds an enhancer element within the PNPLA3 gene (identified by ChIP and luciferase assays) and induces PNPLA3 expression; CRISPR-Cas9 deletion of this ER-α binding site abolishes ER-α-driven PNPLA3 I148M upregulation and the resulting lipid droplet accumulation and fibrogenesis in 3D multilineage liver spheroids. Chromatin immunoprecipitation (ChIP); luciferase assays; CRISPR-Cas9 genome editing of ER-α binding site; 3D liver spheroids with hepatocytes and stellate cells; ER-α agonist treatment Nature medicine High 37749332
2024 BFAR (bifunctional apoptosis regulator), a membrane-bound E3 ubiquitin ligase, co-immunoprecipitates with PNPLA3 and promotes its ubiquitylation in a reconstituted in vitro assay using purified recombinant proteins; siRNA inactivation of BFAR increases endogenous PNPLA3 in hepatocytes, and Bfar knockout mice have 2-fold higher PNPLA3 protein on hepatic LDs with no change in mRNA, establishing BFAR as the E3 ligase responsible for PNPLA3 post-translational turnover. siRNA screen of ubiquitin proteasome components; co-immunoprecipitation; in vitro ubiquitylation reconstitution with purified proteins; Bfar KO mice; LD fractionation and immunoblotting Proceedings of the National Academy of Sciences of the United States of America High 38294943
2024 PNPLA3(148M) is a gain-of-function mutation that promotes steatosis by sequestering ABHD5 (CGI-58) on lipid droplets, thereby limiting ABHD5 availability to activate ATGL-mediated TG hydrolysis; PNPLA3 itself is activated by ABHD5 in vitro (contradicting prior reports of inhibition); overexpression of ABHD5 reverses hepatic steatosis in Pnpla3(M/M) mice; the LD-accumulation of PNPLA3(148M) — not loss of its enzymatic activity — is required for the pro-steatotic effect. NanoBiT complementation assay for protein-protein interaction in hepatocytes; in vitro TG hydrolysis with purified recombinant proteins ± ABHD5; adenovirus/AAV liver expression in liver-specific Atgl-/- mice and Pnpla3(M/M) mice; hepatic TG quantification Journal of hepatology High 39550037
2024 At endogenous expression levels, PNPLA3 and PNPLA3-I148M are not ER-resident transmembrane proteins but are enriched in lipid droplet, Golgi, and endosomal fractions and associate with phosphoinositides from these compartments; PNPLA3-I148M (but not WT) induces Golgi morphological changes including increased lipid droplet-Golgi contact sites, also observed in primary patient hepatocytes. Isogenic CRISPR knockin hepatoma cell lines expressing endogenous PNPLA3/I148M; subcellular fractionation; immunocytochemistry; phosphoinositide binding with purified proteins; proteomics and transcriptomics; primary human hepatocyte imaging Proceedings of the National Academy of Sciences of the United States of America High 38657050
2024 The TM6SF2 E167K variant increases the physical interaction between TM6SF2 and PNPLA3, impairing PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from triglycerides to phosphatidylcholine (PC); this results in decreased polyunsaturated PC and increased polyunsaturated TG, exacerbating hepatic steatosis and oxidative stress. Tm6sf2(167K) knockin mice on HFD; lipidomics; thin-layer chromatography for newly synthesized TG and PC; co-immunoprecipitation of TM6SF2 and PNPLA3 Clinical and molecular hepatology Medium 39054606
2024 HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function (respiratory chain complex IV insufficiency), reduced antioxidant capacity, increased ROS secretion, and decreased NR4A1 (endogenous TGF-β1 inhibitor) expression and activation, leading to enhanced TGF-β1 signaling and fibrogenesis; these defects are exacerbated in 3D cirrhotic extracellular matrix scaffolds. RNA sequencing of primary human HSCs and liver biopsies; 3D ECM scaffold cultures from human healthy and cirrhotic livers; mitochondrial complex activity assays; ROS measurement; NR4A1 agonist (cytosporone B) treatment Journal of hepatology Medium 38365182
2019 ASO-mediated hepatic silencing of Pnpla3 in Pnpla3(148M/M) knockin mice reduces liver steatosis, inflammation score, and fibrosis stage (but not in WT mice), demonstrating that the 148M protein specifically drives NAFLD/NASH/fibrosis and that its knockdown is therapeutic. GalNAc3-conjugated ASO treatment in Pnpla3(148M/M) knockin mice on steatogenic and NASH-inducing diets; liver histology scoring; Mcp1 and Timp2 mRNA quantification Molecular metabolism High 30772256

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 759 21381068
2010 Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 535 20373368
2010 A feed-forward loop amplifies nutritional regulation of PNPLA3. Proceedings of the National Academy of Sciences of the United States of America 307 20385813
2009 A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. Journal of lipid research 305 19738004
2014 Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology (Baltimore, Md.) 299 24917523
2006 Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes 290 16380488
2009 A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 249 19224197
2005 Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. Journal of lipid research 247 16150821
2019 Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proceedings of the National Academy of Sciences of the United States of America 244 31019090
2016 PNPLA3 gene in liver diseases. Journal of hepatology 221 27038645
2010 Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology (Baltimore, Md.) 211 20648554
2001 Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. The Journal of biological chemistry 207 11431482
2013 PNPLA3 I148M polymorphism and progressive liver disease. World journal of gastroenterology 204 24222941
2010 Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. Journal of lipid research 202 21068004
2014 Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology (Baltimore, Md.) 196 24114809
2020 Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population. Hepatology (Baltimore, Md.) 187 32190914
2010 A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology (Baltimore, Md.) 182 20803499
2019 PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice. Hepatology (Baltimore, Md.) 179 30802989
2019 Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Molecular metabolism 175 30772256
2011 Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. The American journal of clinical nutrition 130 21525193
2015 PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. Journal of gastroenterology and hepatology 127 25040896
2015 PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease. The American journal of gastroenterology 125 25964223
2022 IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease. Journal of hepatology 105 36049612
2023 Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nature medicine 98 37749332
2018 The role of PNPLA3 in health and disease. Biochimica et biophysica acta. Molecular and cell biology of lipids 90 29935383
2012 A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Human genetics 90 22258181
2021 TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cellular and molecular gastroenterology and hepatology 88 34823063
2015 Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations. Journal of hepatology 81 25678388
2004 Adiponutrin: A new gene regulated by energy balance in human adipose tissue. The Journal of clinical endocrinology and metabolism 75 15181042
2019 Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) susceptibility and severity: A meta-analysis. Medicine 73 30762732
2013 PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Seminars in liver disease 72 24222094
2011 Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. PLoS genetics 71 21533024
2020 Effect of Gut Microbiota and PNPLA3 rs738409 Variant on Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth. The Journal of clinical endocrinology and metabolism 70 32561908
2019 PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels. Liver international : official journal of the International Association for the Study of the Liver 68 31519069
2010 Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. Journal of hepatology 68 21168459
2014 Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Alimentary pharmacology & therapeutics 66 25060292
2008 Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity. European journal of endocrinology 66 18728122
2021 PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date. Expert opinion on therapeutic targets 62 34904923
2017 PNPLA3 expression and its impact on the liver: current perspectives. Hepatic medicine : evidence and research 62 29158695
2023 The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell metabolism 59 37909034
2022 Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality. JAMA network open 59 36190732
2017 The Expression of PNPLA3 Polymorphism could be the Key for Severe Liver Disease in NAFLD in Hispanic Population. Annals of hepatology 58 29055919
2019 Relationship Between PNPLA3 rs738409 Polymorphism and Decreased Kidney Function in Children With NAFLD. Hepatology (Baltimore, Md.) 57 30912854
2013 PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 57 23333103
2013 A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring, Md.) 57 23512881
2020 A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank. Journal of hepatology 53 32145261
2014 The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis. Journal of lipid research 53 25378656
2009 A common variant in the adiponutrin gene influences liver enzyme values. Journal of medical genetics 52 19542081
2006 Adiponutrin gene is regulated by insulin and glucose in human adipose tissue. European journal of endocrinology 51 16914601
2015 PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis. Journal of gastroenterology and hepatology 50 25641744
2012 PNPLA3 gene-by-visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: the NHLBI family heart study. International journal of obesity (2005) 48 22546774
2021 Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD. The American journal of gastroenterology 47 33306506
2009 Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins. Human molecular genetics 47 19729411
2021 Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. BMC endocrine disorders 46 34147109
2012 PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease. World journal of gastroenterology 46 23155331
2023 Impact of PNPLA3 rs738409 Polymorphism on the Development of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 44 37149016
2015 PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World journal of gastroenterology 39 25624712
2024 PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. Journal of hepatology 38 39550037
2014 PNPLA3 in end-stage liver disease: alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival. Journal of gastroenterology and hepatology 38 25273282
2025 AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. Journal of hepatology 35 39798707
2019 PNPLA3 I148M Variant Impairs Liver X Receptor Signaling and Cholesterol Homeostasis in Human Hepatic Stellate Cells. Hepatology communications 30 31497741
2018 Genetic variants in COL13A1, ADIPOQ and SAMM50, in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population. Experimental and molecular pathology 30 29307798
2004 Macronutrient composition of the diet differentially affects leptin and adiponutrin mRNA expression in response to meal feeding. The Journal of nutritional biochemistry 30 15068818
2024 Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models. Journal of hepatology 29 38365182
2016 PNPLA3 rs738409 Polymorphism Associated with Hepatic Steatosis and Advanced Fibrosis in Patients with Chronic Hepatitis C Virus: A Meta-Analysis. Gut and liver 29 26419236
2013 No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PloS one 29 24349054
2020 Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. Liver international : official journal of the International Association for the Study of the Liver 28 32043752
2010 Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin. Biochemical and biophysical research communications 27 21036152
2007 Regulation of adiponutrin expression by feeding conditions in rats is altered in the obese state. Obesity (Silver Spring, Md.) 27 17372308
2022 Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice. Cell reports 25 36103835
2024 PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic dysfunction-associated steatotic liver disease. Hepatology (Baltimore, Md.) 24 38652636
2024 The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics. Proceedings of the National Academy of Sciences of the United States of America 24 38657050
2024 Impact of PNPLA3 I148M on Clinical Outcomes in Patients With MASLD. Liver international : official journal of the International Association for the Study of the Liver 24 39412170
2021 PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19. Frontiers in cell and developmental biology 24 34249902
2015 Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B. World journal of gastroenterology 24 26229402
2009 Genetic variance in the adiponutrin gene family and childhood obesity. PloS one 24 19390624
2021 Greater liver PNPLA3 protein abundance in vivo and in vitro supports lower triglyceride accumulation in dairy cows. Scientific reports 23 33531537
2020 Independent and joint correlation of PNPLA3 I148M and TM6SF2 E167K variants with the risk of coronary heart disease in patients with non-alcoholic fatty liver disease. Lipids in health and disease 22 32093693
2017 The rs738409 polymorphism of the PNPLA3 gene is associated with hepatic steatosis and fibrosis in Brazilian patients with chronic hepatitis C. BMC infectious diseases 22 29258449
2015 PNPLA3 genetic variation in alcoholic steatosis and liver disease progression. Hepatobiliary surgery and nutrition 22 26151055
2014 Associations of I148M variant in PNPLA3 gene with plasma ALT levels during 2-year follow-up in normal weight and overweight children: the PANIC Study. Pediatric obesity 21 24916969
2024 Global Epidemiology and Implications of PNPLA3 I148M Variant in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. Journal of clinical and experimental hepatology 20 39882540
2021 Combined analysis of gut microbiota, diet and PNPLA3 polymorphism in biopsy-proven non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver 20 33896117
2020 PNPLA3 I148M Up-Regulates Hedgehog and Yap Signaling in Human Hepatic Stellate Cells. International journal of molecular sciences 20 33218077
2019 Correlation between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma: a meta-analysis of 10,330 subjects. The International journal of biological markers 20 30852978
2019 Interaction of TM6SF2 E167K and PNPLA3 I148M variants in NAFLD in northeast China. Annals of hepatology 19 31054977
2017 AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M. Scientific reports 19 29116096
2022 KHK, PNPLA3 and PPAR as Novel Targets for the Anti-Steatotic Action of Bempedoic Acid. Biomedicines 18 35884822
2021 Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease. Nucleic acid therapeutics 18 34297902
2014 Targeted next-generation sequencing and fine linkage disequilibrium mapping reveals association of PNPLA3 and PARVB with the severity of nonalcoholic fatty liver disease. Journal of human genetics 18 24621583
2024 TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD. Clinical and molecular hepatology 16 39054606
2019 PNPLA3 I148M Polymorphism in Patients with Nonalcoholic Fatty Liver Disease, Obesity and Prediabetes. Journal of gastrointestinal and liver diseases : JGLD 15 31826069
2017 Binge alcohol alters PNPLA3 levels in liver through epigenetic mechanism involving histone H3 acetylation. Alcohol (Fayetteville, N.Y.) 15 28433418
2009 Tri-iodothyronine upregulates adiponutrin mRNA expression in rat and human adipocytes. Molecular and cellular endocrinology 15 19619606
2025 Experimental Models to Investigate PNPLA3 in Liver Steatosis. Liver international : official journal of the International Association for the Study of the Liver 14 40231787
2015 The SRE Motif in the Human PNPLA3 Promoter (-97 to -88 bp) Mediates Transactivational Effects of SREBP-1c. Journal of cellular physiology 14 25655569
2014 Adiponutrin: a multimeric plasma protein. Biochemical and biophysical research communications 14 24680680
2024 The ubiquitin E3 ligase BFAR promotes degradation of PNPLA3. Proceedings of the National Academy of Sciences of the United States of America 13 38294943
2021 Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer. Cancers 13 34503201
2019 PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression. Archives of physiology and biochemistry 13 31793339