Affinage

PNPLA3

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

Length
481 aa
Mass
52.9 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PNPLA3 is a lipid droplet-associated serine hydrolase that governs the remodeling of stored neutral lipids in hepatocytes and hepatic stellate cells, and its common I148M variant is a principal driver of fatty liver disease (PMID:21878620, PMID:39550037). The purified enzyme hydrolyzes triacylglycerol, diacylglycerol, and monoacylglycerol with preference for oleate and additionally catalyzes acyltransferase reactions, activities that depend on its catalytic serine and are largely lost by the I148M substitution (PMID:21878620, PMID:24369119). Mechanistically, PNPLA3 mediates fatty acid-selective remodeling of triglycerides, transferring polyunsaturated fatty acids from triglyceride/diacylglycerol pools toward phosphatidylcholine synthesis; I148M impairs this transacylation, depleting VLDL-triglycerides of PUFAs and causing accumulation of PUFA-containing diacylglycerols (PMID:24511104, PMID:31434800). In hepatic stellate cells PNPLA3 instead hydrolyzes retinyl palmitate to release retinol, an activity also lost in the I148M protein (PMID:24670599). The decisive lesion in disease is not loss of catalysis but accumulation of the protein on lipid droplets: a ubiquitylation-resistant PNPLA3 that retains enzymatic activity still causes steatosis, establishing droplet accumulation itself as the steatotic driver (PMID:31019090). This accumulation reflects escape from turnover normally imposed by the membrane-bound E3 ubiquitin ligase BFAR, which ubiquitylates PNPLA3 to direct its proteasomal/autophagic degradation (PMID:38294943). Accumulated PNPLA3 acts as a gain-of-function inhibitor of ATGL-mediated lipolysis by binding and sequestering the ATGL cofactor ABHD5/CGI-58; CGI-58 is required for PNPLA3 localization to droplets and for I148M-driven steatosis, and ABHD5 overexpression reverses steatosis in I148M mice (PMID:30802989, PMID:39550037). Beyond steatosis, the I148M variant drives the progression of liver disease through stellate-cell mitochondrial dysfunction, disrupted LXR-dependent cholesterol homeostasis, and activation of NF-κB and IL-6/STAT3 pro-inflammatory and pro-fibrogenic signaling (PMID:31497741, PMID:36049612, PMID:37298640). PNPLA3 expression is transcriptionally controlled by nutritional and hormonal cues, including glucose/insulin and estrogen receptor-α acting at a hepatic enhancer (PMID:16150821, PMID:21036152, PMID:37749332).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2001 Medium

    Established PNPLA3 as a nutritionally regulated, membrane-associated protein, framing it as a metabolic effector rather than a cytosolic enzyme.

    Evidence Western blot and confocal imaging of epitope-tagged protein in adipocyte/COS cells with nutritional regulation in vivo

    PMID:11431482

    Open questions at the time
    • Did not define enzymatic activity or substrate
    • Adipose-restricted view later revised by hepatic and stellate-cell findings
  2. 2005 Medium

    Showed PNPLA3 possesses intrinsic serine-dependent lipase activity yet does not drive net cellular lipolysis, distinguishing it from ATGL.

    Evidence In vitro lipase assay with recombinant protein, active-site serine mutant, and cell-based triglyceride quantification

    PMID:16150821

    Open questions at the time
    • Did not resolve physiological substrate
    • Disconnect between in vitro activity and cellular phenotype unexplained
  3. 2006 Medium

    Confirmed PNPLA3 is dispensable for adipocyte lipolysis and is regulated oppositely to ATGL by insulin, sharpening its functional separation from canonical lipases.

    Evidence siRNA knockdown with glycerol/NEFA lipolysis readout and insulin dose-response in 3T3-L1 adipocytes

    PMID:16380488

    Open questions at the time
    • No insight into hepatic role
    • Substrate and direction of acyl chemistry unresolved
  4. 2010 High

    Demonstrated that loss of PNPLA3 function alone does not cause fatty liver, redirecting the field away from a simple loss-of-function model.

    Evidence Gene-targeted knockout mice across multiple dietary and ob/ob challenges with liver TG and metabolic phenotyping

    PMID:20648554 PMID:21068004

    Open questions at the time
    • Did not explain how the human I148M variant causes disease
    • Implied a gain-of-function or species-specific mechanism not yet defined
  5. 2010 Medium

    Defined transcriptional control of PNPLA3 by glucose and insulin, linking its expression to nutritional state at the promoter level.

    Evidence Luciferase promoter reporter assays in HepG2/CHO-IR cells with USF2 co-transfection and non-metabolizable glucose control

    PMID:21036152

    Open questions at the time
    • Single transcription factor (USF2) tested
    • Did not connect expression level to disease phenotype
  6. 2011 High

    Reconstituted PNPLA3 as a glycerolipid hydrolase with oleate preference and showed I148M reduces Vmax, providing the first biochemical definition of the disease variant's enzymatic defect.

    Evidence Purified recombinant protein, radiometric assays, catalytic-serine and I148M mutagenesis, substrate panel

    PMID:21878620

    Open questions at the time
    • Loss of activity insufficient given KO mouse data
    • No phospholipid or retinyl ester activity detected in this assay
  7. 2013 High

    Independently confirmed triglyceride lipase activity (plus mild LPAAT activity) and the I148M loss-of-function, while localizing PNPLA3 to lipid droplets via the Brummer-box domain with droplet-size phenotypes.

    Evidence Pichia-expressed purified protein assays; subcellular fractionation, imaging, domain-deletion and ABHD5 co-expression in cells

    PMID:23398201 PMID:24369119

    Open questions at the time
    • Mechanism linking droplet localization to enlargement unresolved
    • Role of ABHD5 interaction not yet characterized
  8. 2014 High

    Revealed two tissue-specific catalytic roles: fatty acid-selective TAG remodeling in hepatocytes and retinyl-palmitate hydrolysis in stellate cells, both impaired by I148M.

    Evidence Isotope pulse-chase/lipidomics in HuH7 cells; purified-protein retinyl ester assay, primary human HSCs, and human cohort RBP4 correlation

    PMID:24511104 PMID:24670599

    Open questions at the time
    • Did not establish whether remodeling defect alone causes steatosis
    • Connection between hepatocyte and stellate-cell roles unclear
  9. 2016 Medium

    Linked PNPLA3 retinoid metabolism to fibrogenic output, showing WT but not I148M suppresses MMP2/TIMP secretion and that TGF-β induces PNPLA3 in stellate cells.

    Evidence Stable overexpression in LX-2 cells and primary HSCs with ELISA, retinol measurement, siRNA, and TGF-β treatment

    PMID:27742777

    Open questions at the time
    • Causal chain from retinoid defect to fibrosis incomplete
    • Single cell-line/primary-cell system
  10. 2019 High

    Overturned the loss-of-function paradigm by showing droplet accumulation of PNPLA3 itself, independent of catalytic activity, causes steatosis, and that degrading PNPLA3 reverses it.

    Evidence AAV/adenoviral overexpression in mice, ubiquitylation-resistant and catalytically dead constructs, shRNA and PROTAC degradation, liver TG and LD imaging

    PMID:31019090

    Open questions at the time
    • Molecular consequence of droplet accumulation not yet defined
    • Identity of the turnover machinery unknown at this point
  11. 2019 High

    Identified the gain-of-function mechanism: PNPLA3 binds CGI-58/ABHD5, requires it for droplet localization, and sequesters it from ATGL to inhibit lipolysis.

    Evidence Reciprocal Co-IP, in vitro pulldown with purified proteins, liver-specific Cgi-58 KO epistasis, and HuH-7 overexpression

    PMID:30802989

    Open questions at the time
    • Stoichiometry and preferential binding versus ATGL not yet quantified
    • How accumulation is achieved physiologically unresolved
  12. 2019 High

    Pinpointed the in vivo human metabolic defect of I148M as impaired transfer of PUFAs from DAG/TG toward phosphatidylcholine, depleting VLDL-TG of PUFAs.

    Evidence Stable isotope tracers in homozygous I148M humans plus isogenic genotype-edited human cells with lipidomics

    PMID:31434800

    Open questions at the time
    • Relationship between transacylation defect and droplet accumulation not integrated
    • Tissue-specific contribution of liver vs adipose unclear
  13. 2019 High

    Demonstrated genotype-dependent reversibility, with ASO silencing of mutant PNPLA3 reducing steatosis, inflammation, and fibrosis in I148M knock-in mice.

    Evidence GalNAc3-ASO liver-targeted silencing in Pnpla3-I148M knock-in mice with histological scoring

    PMID:30772256

    Open questions at the time
    • Fibrosis effect not seen in WT controls
    • Downstream signaling mediators not defined here
  14. 2019 Medium

    Connected PNPLA3-I148M to hepatocyte inflammation via NF-κB (which also drives PNPLA3 transcription) and an ER-stress IRE-1α/JNK/c-Jun axis.

    Evidence Luciferase, EMSA/supershift, ChIP-qPCR, siRNA, and stable overexpression in hepatocyte models

    PMID:31793207

    Open questions at the time
    • Single lab
    • Causal contribution to in vivo inflammation not isolated
  15. 2019 Medium

    Showed I148M disrupts LXR-dependent cholesterol homeostasis in stellate cells and that an LXR agonist restores function and reduces fibrogenic gene expression.

    Evidence Genotype-stratified primary human HSCs with LXR luciferase reporter, target qPCR, cholesterol assays, and T0901317 treatment

    PMID:31497741

    Open questions at the time
    • No independent replication
    • Mechanistic link from lipase defect to LXR dysfunction not defined
  16. 2020 Medium

    Quantified PNPLA3 as highly abundant in human adipose tissue and showed I148M remodels adipose TGs toward PUFA enrichment without altering lipolysis.

    Evidence Paired liver/adipose protein quantification, AT lipidomics, and glycerol tracer in genotype-stratified humans

    PMID:32386450

    Open questions at the time
    • Functional consequence of adipose remodeling for systemic disease unclear
    • Single lab
  17. 2020 Medium

    Defined stellate-cell mitochondrial dysfunction as a fibrogenic consequence of I148M, driven by free-cholesterol accumulation and altered TGF-β/NR4A1 signaling with elevated ROS.

    Evidence RNA-seq, 3D ECM and LX-2 culture, Seahorse respirometry, cholesterol efflux assays, signaling inhibitors

    PMID:37298640 PMID:38365182

    Open questions at the time
    • Single-lab cell models
    • Direct link from enzyme defect to mitochondrial damage not fully reconstituted
  18. 2022 Medium

    Established IL-6/STAT3 as a causal pro-NAFLD pathway downstream of I148M using an isogenic multicellular human liver system with bidirectional manipulation.

    Evidence hPSC-derived multicellular liver organoids, CRISPR isogenic rs738049 editing, IL-6/STAT3 inhibition and activation, human transcriptomic corroboration

    PMID:36049612

    Open questions at the time
    • Single model system
    • Upstream trigger connecting PNPLA3 to IL-6/STAT3 not defined
  19. 2023 High

    Identified estrogen receptor-α binding at a hepatic enhancer as a sex-dependent transcriptional driver of PNPLA3, providing a mechanism for sex differences in expression and fibrogenesis.

    Evidence ChIP, luciferase, CRISPR deletion of the ER-α site, and 3D multilineage spheroid functional validation

    PMID:37749332

    Open questions at the time
    • Quantitative contribution to clinical sex differences not established
    • Interaction with nutritional regulators not integrated
  20. 2023 High

    Demonstrated I148M causes hepatic mitochondrial dysfunction in humans, shifting fatty acids toward ketogenesis and reducing de novo lipogenesis and citrate synthase flux.

    Evidence Deuterium water and 13C-acetate tracers with mitochondrial redox measurements in genotype-stratified humans under ketogenic challenge

    PMID:37909034

    Open questions at the time
    • Causal link from droplet accumulation to mitochondrial change not mechanistically traced
    • Hepatocyte vs stellate-cell contributions not separated
  21. 2024 High

    Identified BFAR as the E3 ligase that ubiquitylates PNPLA3 for degradation, explaining how mutant protein evades turnover to accumulate on droplets.

    Evidence Ubiquitin-proteasome siRNA screen, Co-IP, in vitro ubiquitylation reconstitution with purified proteins, and Bfar KO mice

    PMID:38294943

    Open questions at the time
    • Whether I148M specifically resists BFAR-mediated ubiquitylation not fully quantified
    • Relative roles of proteasomal vs autophagic disposal unresolved
  22. 2024 High

    Provided the definitive gain-of-function model: PNPLA3 preferentially binds ABHD5 over ATGL, requires ATGL and droplet localization for steatosis, and ABHD5 overexpression reverses the phenotype.

    Evidence NanoBiT interaction assays, in vitro TG hydrolysis with purified proteins ± ABHD5, liver-specific Atgl-/- mice, and ABHD5 rescue in Pnpla3 M/M mice

    PMID:39550037

    Open questions at the time
    • Structural basis of ABHD5 preference unresolved
    • Integration with transacylation defect mechanism not fully reconciled
  23. 2024 High

    Revised the subcellular localization model, showing endogenous PNPLA3 is enriched in lipid droplet, Golgi, and endosomal fractions rather than the ER, and that I148M alters Golgi morphology and LD-Golgi contacts.

    Evidence Isogenic endogenous-expression hepatoma lines, fractionation, immunofluorescence, EM, phosphoinositide binding, proteomics, and primary patient hepatocytes

    PMID:38657050

    Open questions at the time
    • Functional role of Golgi/endosomal pools unclear
    • Significance of LD-Golgi contact sites for disease undefined
  24. 2024 Medium

    Linked PNPLA3 to TM6SF2 genetically, showing the TM6SF2-E167K variant enhances TM6SF2-PNPLA3 interaction and impairs PNPLA3-mediated PUFA transfer from TG to PC.

    Evidence Tm6sf2-E167K knock-in mice on high-fat diet, lipidomics, TLC of newly synthesized lipids, and Co-IP

    PMID:39054606

    Open questions at the time
    • Single lab
    • Whether TM6SF2 modulates PNPLA3 in humans not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the transacylation/PUFA-remodeling defect, droplet accumulation with ABHD5 sequestration, and downstream mitochondrial and pro-fibrogenic signaling are causally integrated into a single quantitative mechanism remains unresolved.
  • No structure of PNPLA3 or PNPLA3-ABHD5 complex in the corpus
  • Causal order linking droplet accumulation to mitochondrial and signaling phenotypes not established
  • Therapeutic degradation strategies not validated clinically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005811 lipid droplet 4 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ABHD5ATGLBFARTM6SF2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Adiponutrin (PNPLA3) is a transmembrane protein that strictly localizes to membranes and is absent from the cytosol, as shown by Western blot and confocal imaging of epitope-tagged protein in 3T3-L1 adipocytes and COS cells. Its expression is exclusively in the adipose lineage and is tightly regulated by nutritional state (downregulated by fasting, dramatically induced by refeeding a high-carbohydrate diet). Western blot; confocal immunofluorescence imaging of epitope-tagged protein; mRNA differential display; Northern blot The Journal of biological chemistry Medium 11431482
2005 Recombinant adiponutrin (PNPLA3) displays lipase activity in vitro that is dependent on the presence of the active-site serine; however, unlike ATGL/Desnutrin, overexpression of adiponutrin does not decrease intracellular triglyceride levels in cells, indicating it does not contribute to net lipolysis. In vitro lipase assay with recombinant proteins; active-site serine mutation; cell-based overexpression with intracellular triglyceride quantification Journal of lipid research Medium 16150821
2006 siRNA-mediated knockdown of adiponutrin (PNPLA3) in 3T3-L1 adipocytes had no effect on glycerol or NEFA release, indicating adiponutrin does not contribute to net adipocyte lipolysis. Adiponutrin is oppositely regulated by insulin compared to ATGL (insulin increases adiponutrin and decreases ATGL expression). siRNA knockdown; lipolysis assay (glycerol and NEFA measurement); insulin dose-response in 3T3-L1 adipocytes; in vivo streptozotocin diabetic mouse model Diabetes Medium 16380488
2011 Purified recombinant human PNPLA3 hydrolyzes triacylglycerol, diacylglycerol, and monoacylglycerol with preference for oleic acid as acyl moiety, and also catalyzes oleoyl-CoA thioesterase activity. The I148M substitution markedly decreases Vmax for glycerolipid substrates (loss of function) but has only modest effect on Km. PNPLA3 shows little to no hydrolytic activity against phospholipids, cholesteryl ester, or retinyl esters (by this assay), and neither WT nor I148M catalyzes de novo TAG synthesis. Purified recombinant protein; radiometric in vitro enzymatic assay; site-directed mutagenesis (catalytic serine; I148M); substrate specificity profiling The Journal of biological chemistry High 21878620
2010 Germline knockout of Pnpla3 in mice does not cause fatty liver, elevated liver enzymes, or insulin resistance under normal chow, high-fat diet, high-sucrose diet, or in the ob/ob background, indicating loss of PNPLA3 function alone is insufficient to cause fatty liver in mice. Gene-targeted Pnpla3 knockout mouse; liver triglyceride measurement; plasma AST/ALT; glucose/insulin tolerance tests; multiple dietary challenges Hepatology (Baltimore, Md.) High 20648554 21068004
2013 Purified recombinant PNPLA3 (expressed in Pichia pastoris) shows predominant triglyceride lipase activity and mild lysophosphatidic acid acyltransferase (LPAAT) activity; the I148M mutation results in loss of function of both activities. Pichia pastoris expression system; Ni-affinity protein purification; in vitro enzymatic assay with radiolabeled substrates; I148M mutant comparison Biochimica et biophysica acta High 24369119
2013 PNPLA3 localizes to lipid droplets (LDs) via a process requiring an intact Brummer box domain. The NAFLD-linked I148M isoform leads to larger LDs upon overexpression, whereas decreased PNPLA3 levels produce smaller LDs. Co-expression of PNPLA3 with ABHD5/CGI-58 induces LD size reduction. Subcellular fractionation; immunofluorescence; live-cell imaging; overexpression and siRNA knockdown in fibroblast-like cells supplemented with lipids; domain deletion constructs Biology of the cell Medium 23398201
2014 Purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid in human hepatic stellate cells (HSCs). The I148M variant markedly reduces this retinyl-palmitate lipase activity. PNPLA3 is highly expressed in HSCs, its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression reduces lipid droplet content and promotes extracellular retinol release. Purified recombinant protein enzymatic assay; primary human HSC culture; siRNA knockdown; overexpression; retinol measurement; PNPLA3 genotype correlation with circulating retinol-binding protein 4 in human cohort Human molecular genetics High 24670599
2014 PNPLA3 mediates fatty acid-selective remodeling of triacylglycerols in hepatocytes. WT PNPLA3 accelerates turnover of oleic acid-labeled TAGs, while I148M impairs this activity and preferentially accumulates on lipid droplets compared to WT (which distributes more to ER/cytosol), consistent with impaired TAG remodeling causing lipid accumulation. 13C-glycerol isotope labeling; D17-oleic acid pulse-chase; lipidomics; principal component analysis; subcellular fractionation; overexpression of WT and I148M in HuH7 cells Journal of lipid research Medium 24511104
2016 In human hepatic stellate cells (LX-2), stable overexpression of WT PNPLA3 (but not I148M mutant) reduces secretion of MMP2, TIMP1, and TIMP2, and this effect is mediated through retinoid metabolism. TGF-β upregulates PNPLA3 expression in HSCs and is involved in TGF-β-induced lipid droplet reduction. Retinol release from primary human HSCs is lower in cells with I148M compared to WT. Stable lentiviral overexpression in LX-2 cells; primary human HSC culture; ELISA for MMP2/TIMP1/TIMP2; retinol measurement; siRNA knockdown; TGF-β treatment Human molecular genetics Medium 27742777
2019 PNPLA3(I148M) and the catalytically dead S47A mutant accumulate on hepatic lipid droplets when expressed in sucrose-fed mice and cause TG accumulation. Expression of a ubiquitylation-resistant form of PNPLA3 (which accumulates on LDs without loss of enzymatic activity) also causes fatty liver, demonstrating that LD accumulation of PNPLA3 itself—not loss of enzymatic activity—causes steatosis. Knockdown of PNPLA3 by shRNA or PROTAC-mediated degradation reduces liver TG in PNPLA3(148M)-overexpressing mice. AAV/adenoviral overexpression in mice; ubiquitylation-resistant PNPLA3 construct; shRNA knockdown; PROTAC degradation; liver TG measurement; LD immunostaining Proceedings of the National Academy of Sciences of the United States of America High 31019090
2019 PNPLA3 (WT and I148M) interacts directly with CGI-58 (ABHD5), the cofactor of ATGL, as shown by co-immunoprecipitation and in vitro pulldown with purified proteins. PNPLA3 requires CGI-58 for localization to hepatic LDs, and PNPLA3(148M)-induced steatosis requires CGI-58 presence. Co-expression of PNPLA3 with CGI-58 depletes LDs, consistent with PNPLA3 inhibiting ATGL by sequestering CGI-58. Co-immunoprecipitation in mouse liver and cultured cells; in vitro pulldown with purified proteins; liver-specific Cgi-58 KO mice; overexpression in HuH-7 cells; liver TG measurement Hepatology (Baltimore, Md.) High 30802989
2019 In homozygous PNPLA3-I148M humans, VLDL-triglycerides are depleted of polyunsaturated fatty acids (PUFAs) under fasting and postprandial conditions. In PNPLA3-148M and PNPLA3-KO human cells, PUFA incorporation into TGs is increased at the expense of phosphatidylcholines, and PUFA-containing DAGs accumulate under lipolytic conditions compared to 148I cells. This establishes I148M as a loss-of-function allele that impairs hydrolysis/transacylation of PUFAs from DAGs to feed PC synthesis. Stable isotope tracer studies in humans; lipidomics in human cells with PNPLA3 genotype editing; VLDL-TG fatty acid composition in vivo; DAG accumulation assay JCI insight High 31434800
2019 ASO-mediated silencing of Pnpla3 in Pnpla3-I148M knock-in mice reduces liver steatosis, inflammation score, and fibrosis stage on a NASH-inducing diet (but not in WT littermates for fibrosis). This establishes that the steatosis and fibrosis phenotype associated with PNPLA3-I148M is dependent on expression of the mutant protein. GalNAc3-conjugated ASO liver-targeted silencing; Pnpla3-I148M knock-in mouse model; liver histology scoring (steatosis, inflammation, fibrosis); Mcp1 and Timp2 mRNA measurement Molecular metabolism High 30772256
2019 PNPLA3 I148M mediates NF-κB-driven inflammation in hepatocytes. NF-κB (p65/p50) binds a site in the PNPLA3 promoter to drive transcription; PNPLA3 silencing blocks NF-κB- or palmitic acid-induced TNF-α upregulation; mutant (but not WT) PNPLA3 overexpression activates the ER stress IRE-1α/JNK/c-Jun inflammatory pathway independently of NF-κB. Luciferase reporter assay; EMSA; ChIP-qPCR; siRNA knockdown; stable lentiviral overexpression; supershift analysis confirming p65/p50 complex Journal of cellular and molecular medicine Medium 31793207
2019 In primary I148M HSCs, LXRα protein is elevated but LXR target gene expression is reduced, LXR transcriptional activity is decreased, and cholesterol efflux is diminished while free cholesterol accumulates. The synthetic LXR agonist T0901317 restores LXR functionality and reduces pro-fibrogenic gene expression in I148M HSCs. Primary human HSC culture stratified by PNPLA3 genotype; LXR luciferase reporter assay; qRT-PCR of LXR targets; cholesterol assays; LXR agonist treatment Hepatology communications Medium 31497741
2020 PNPLA3 is highly abundant at the protein level in human adipose tissue (3-fold higher per tissue protein than liver). PNPLA3-I148M locally remodels adipose tissue TGs to become enriched in polyunsaturated species (PUFA-TGs increased in AT of variant carriers) without altering the rate of lipolysis or serum NEFA composition. PNPLA3 mRNA and protein quantification in paired liver and adipose tissue biopsies; AT lipidomics; [2H5]glycerol lipolysis tracer; genotype-stratified comparison Liver international Medium 32386450
2022 The I148M variant drives enhanced NAFLD phenotype development through elevated IL-6/STAT3 and NF-κB activity in an isogenic hPSC-derived multicellular liver culture (hepatocytes, stellate cells, macrophages). Dampening IL-6/STAT3 activity alleviated I148M-mediated NAFLD phenotypes; boosting IL-6/STAT3 in WT cultures enhanced NAFLD, establishing a causal link. Isogenic hPSC-derived multicellular liver organoid system; CRISPR-Cas9 isogenic editing of rs738049; IL-6/STAT3 pathway inhibition/activation; transcriptomic analysis corroborated with human liver biopsy data Journal of hepatology Medium 36049612
2023 Estrogen receptor-α (ER-α) binds a functional enhancer element within the PNPLA3 locus to upregulate PNPLA3 expression. CRISPR-Cas9 deletion of this ER-α-binding site reduces PNPLA3-I148M upregulation and attenuates lipid droplet accumulation and fibrogenesis in 3D multilineage spheroids with stellate cells. Hepatic PNPLA3 expression is higher in women than men in obesity and correlates with estrogen levels in mice. Chromatin immunoprecipitation (ChIP); luciferase reporter assay; CRISPR-Cas9 genome editing of ER-α binding site; 3D multilineage liver spheroids; hepatocyte and liver organoid treatment with ER-α agonists Nature medicine High 37749332
2023 Homozygous PNPLA3 I148M carriers have higher plasma β-hydroxybutyrate, lower hepatic de novo lipogenesis (DNL), and increased channeling of fatty acids toward ketogenesis associated with hepatic mitochondrial redox changes and decreased mitochondrial citrate synthase flux, demonstrating that the variant causes hepatic mitochondrial dysfunction. Stable isotope tracer studies (deuterium water for DNL; 13C acetate for ketogenesis); hepatic mitochondrial redox measurements; ketogenic diet challenge; genotype-stratified human study Cell metabolism High 37909034
2024 BFAR (bifunctional apoptosis regulator), a membrane-bound E3 ubiquitin ligase, promotes ubiquitylation and proteasomal/autophagic degradation of PNPLA3. BFAR and PNPLA3 co-immunoprecipitate when co-expressed; BFAR promotes PNPLA3 ubiquitylation in a reconstitution assay with purified proteins; BFAR knockdown increases PNPLA3 levels and Bfar KO mice show increased PNPLA3 protein on hepatic LDs without increased mRNA. siRNA screen of ubiquitin proteasome components; co-immunoprecipitation; in vitro ubiquitylation reconstitution assay with purified proteins; Bfar KO mouse; PNPLA3 protein/mRNA quantification 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 hepatic steatosis by accumulating on lipid droplets and sequestering ABHD5 (CGI-58) away from ATGL, thereby inhibiting ATGL-mediated TG hydrolysis. ABHD5 interacts preferentially with PNPLA3 over ATGL in hepatocytes. PNPLA3(WT and 148M) are both activated by ABHD5 in vitro. The steatotic effect requires ATGL expression and LD localization of PNPLA3. Overexpression of ABHD5 in Pnpla3(M/M) mice reverses hepatic steatosis. NanoBiT complementation assay for protein-protein interactions; immunocytochemistry; in vitro TG hydrolysis assay with purified recombinant proteins ± ABHD5; adenoviral/AAV overexpression in liver-specific Atgl-/- mice; ABHD5 overexpression in Pnpla3M/M mice; liver TG measurement 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. PNPLA3-I148M induces morphological changes in the Golgi apparatus including increased lipid droplet-Golgi contact sites, observed both in isogenic hepatoma cells and primary human I148M-expressing hepatocytes. Isogenic CRISPR-engineered human hepatoma cell lines expressing PNPLA3 at endogenous levels; subcellular fractionation; immunofluorescence; electron microscopy; phosphoinositide binding assay with purified protein; proteomics; primary human hepatocytes Proceedings of the National Academy of Sciences of the United States of America High 38657050
2024 TM6SF2 E167K variant increases physical interaction between TM6SF2 and PNPLA3, and impairs PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to phosphatidylcholine (PC), as shown in Tm6sf2-E167K knock-in mice on high-fat diet using lipidomics and TLC-based newly synthesized lipid measurement. Tm6sf2-E167K knock-in mouse; high-fat diet challenge; lipidomics; thin-layer chromatography for newly synthesized TG and PC; co-immunoprecipitation (TM6SF2–PNPLA3 interaction) Clinical and molecular hepatology Medium 39054606
2010 The PNPLA3/adiponutrin promoter is regulated by glucose and insulin: glucose (25 mM) induces promoter activity 4.7-fold in HepG2 cells and 2-fold in CHO cells in a glucose metabolism-dependent manner; insulin has an additive effect in cells expressing the insulin receptor. USF2 transcription factor co-transfection further potentiates insulin-driven promoter activity. Luciferase reporter assay; promoter cloning; CHO-IR cell system; USF2 co-transfection; non-metabolizable glucose analog control Biochemical and biophysical research communications Medium 21036152
2020 In PNPLA3-I148M HSCs, expression and activation of the endogenous TGF-β inhibitor NR4A1 are decreased; NR4A1 regulation by TGF-β/cytosporone B was linked to Akt signaling in WT HSCs but Erk signaling in I148M HSCs. PNPLA3-I148M HSCs show impaired mitochondrial function (respiratory chain complex IV insufficiency), lower antioxidant capacity, increased ROS secretion, and increased TGF-β signaling. RNA sequencing of primary human HSCs and liver biopsies; 3D extracellular matrix scaffold culture; mitochondrial respirometry; ROS measurement; TGF-β and cytosporone B treatment; signaling pathway inhibitors Journal of hepatology Medium 38365182
2020 PNPLA3-I148M in HSCs causes mitochondrial dysfunction through accumulation of free cholesterol (by decreasing ABCG1-mediated cholesterol efflux), leading to attenuated ATP production, decreased mitochondrial membrane potential, elevated ROS, and structural mitochondrial damage, thereby promoting HSC activation and fibrosis. Immunofluorescence; ELISA; real-time PCR; Western blot; electron microscopy; Seahorse XFe96 mitochondrial respirometry; cholesterol efflux assay in LX-2 cells overexpressing I148M vs WT International journal of molecular sciences Medium 37298640

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 539 20373368
2009 A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. Journal of lipid research 308 19738004
2014 PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Human molecular genetics 298 24670599
2006 Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes 290 16380488
2011 Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. The Journal of biological chemistry 259 21878620
2009 A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 250 19224197
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 248 31019090
2005 Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. Journal of lipid research 247 16150821
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.) 214 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 209 11431482
2013 PNPLA3 I148M polymorphism and progressive liver disease. World journal of gastroenterology 208 24222941
2010 Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. Journal of lipid research 204 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
2019 PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice. Hepatology (Baltimore, Md.) 181 30802989
2019 Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Molecular metabolism 178 30772256
2013 Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochimica et biophysica acta 160 24369119
2019 Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI insight 136 31434800
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 129 25040896
2015 PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease. The American journal of gastroenterology 127 25964223
2011 Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. Journal of hepatology 125 21334404
2022 IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease. Journal of hepatology 114 36049612
2016 PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Human molecular genetics 109 27742777
2015 Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Scientific reports 108 25791171
2023 Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nature medicine 106 37749332
2014 PNPLA3 mediates hepatocyte triacylglycerol remodeling. Journal of lipid research 97 24511104
2018 The role of PNPLA3 in health and disease. Biochimica et biophysica acta. Molecular and cell biology of lipids 92 29935383
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 89 34823063
2013 PNPLA3/adiponutrin functions in lipid droplet formation. Biology of the cell 80 23398201
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
2010 Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. Journal of hepatology 68 21168459
2013 Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. Journal of gastroenterology 66 23800943
2008 Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity. European journal of endocrinology 66 18728122
2023 The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell metabolism 65 37909034
2022 Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality. JAMA network open 64 36190732
2021 PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date. Expert opinion on therapeutic targets 64 34904923
2017 PNPLA3 expression and its impact on the liver: current perspectives. Hepatic medicine : evidence and research 63 29158695
2006 Variation in the adiponutrin gene influences its expression and associates with obesity. Diabetes 62 16505250
2019 Relationship Between PNPLA3 rs738409 Polymorphism and Decreased Kidney Function in Children With NAFLD. Hepatology (Baltimore, Md.) 59 30912854
2019 PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease. Frontiers in medicine 59 31921875
2021 Modeling PNPLA3-Associated NAFLD Using Human-Induced Pluripotent Stem Cells. Hepatology (Baltimore, Md.) 57 34288010
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
2014 The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis. Journal of lipid research 54 25378656
2020 PNPLA3 I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: Clinical and experimental findings. Liver international : official journal of the International Association for the Study of the Liver 52 32125756
2009 A common variant in the adiponutrin gene influences liver enzyme values. Journal of medical genetics 52 19542081
2015 PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis. Journal of gastroenterology and hepatology 51 25641744
2006 Adiponutrin gene is regulated by insulin and glucose in human adipose tissue. European journal of endocrinology 51 16914601
2021 Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. BMC endocrine disorders 48 34147109
2009 Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins. Human molecular genetics 47 19729411
2024 PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. Journal of hepatology 46 39550037
2012 PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease. World journal of gastroenterology 46 23155331
2003 Adiponutrin mRNA expression in white adipose tissue is rapidly induced by meal-feeding a high-sucrose diet. Biochemical and biophysical research communications 46 12565853
2025 AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. Journal of hepatology 40 39798707
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 40 25624712
2019 PNPLA3-I148M: a problem of plenty in non-alcoholic fatty liver disease. Adipocyte 37 31062641
2013 Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. Journal of gastroenterology and hepatology 36 23278404
2019 PNPLA3 I148M mediates the regulatory effect of NF-kB on inflammation in PA-treated HepG2 cells. Journal of cellular and molecular medicine 34 31793207
2024 Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models. Journal of hepatology 31 38365182
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.) 30 38652636
2019 PNPLA3 I148M Variant Impairs Liver X Receptor Signaling and Cholesterol Homeostasis in Human Hepatic Stellate Cells. Hepatology communications 30 31497741
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
2018 PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World journal of clinical cases 29 30148144
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
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 27 39412170
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 ChREBP-driven DNL and PNPLA3 Expression Induced by Liquid Fructose are Essential in the Production of Fatty Liver and Hypertriglyceridemia in a High-Fat Diet-Fed Rat Model. Molecular nutrition & food research 26 35124887
2022 Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice. Cell reports 26 36103835
2014 Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells. Metabolism: clinical and experimental 26 25060692
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
2022 PNPLA3 rs738409 and risk of fibrosis in NAFLD: Exploring mediation pathways through intermediate histological features. Hepatology (Baltimore, Md.) 24 35349726
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
2009 Genetic variance in the adiponutrin gene family and childhood obesity. PloS one 24 19390624
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 23 39882540
2021 Greater liver PNPLA3 protein abundance in vivo and in vitro supports lower triglyceride accumulation in dairy cows. Scientific reports 23 33531537
2020 The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue. Liver international : official journal of the International Association for the Study of the Liver 23 32386450
2015 PNPLA3 genetic variation in alcoholic steatosis and liver disease progression. Hepatobiliary surgery and nutrition 23 26151055
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
2020 PNPLA3 gene polymorphism and overall and cardiovascular mortality in the United States. Journal of gastroenterology and hepatology 21 32220085
2020 PNPLA3 Gene Polymorphism and Liver- and Extrahepatic Cancer-Related Mortality in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 21 32360822
2019 Correlation between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma: a meta-analysis of 10,330 subjects. The International journal of biological markers 21 30852978
2011 Diet-induced obesity affects expression of adiponutrin/PNPLA3 and adipose triglyceride lipase, two members of the same family. International journal of obesity (2005) 21 21556044
2023 PNPLA3 I148M and response to treatment for hepatic steatosis: A systematic review. Liver international : official journal of the International Association for the Study of the Liver 20 36719059
2020 PNPLA3 I148M Up-Regulates Hedgehog and Yap Signaling in Human Hepatic Stellate Cells. International journal of molecular sciences 20 33218077
2023 Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 19 38145725
2019 Interaction of TM6SF2 E167K and PNPLA3 I148M variants in NAFLD in northeast China. Annals of hepatology 19 31054977
2024 TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD. Clinical and molecular hepatology 18 39054606
2023 PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction. International journal of molecular sciences 18 37298640
2022 KHK, PNPLA3 and PPAR as Novel Targets for the Anti-Steatotic Action of Bempedoic Acid. Biomedicines 18 35884822
2018 Association between rs738409 polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies. Gene 17 30403964
2017 PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population. Journal of gastrointestinal and liver diseases : JGLD 17 28338112
2013 The adiponutrin I148M variant is a risk factor for HCV-associated liver cancer in North-African patients. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 17 24269995
2024 Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis. Liver international : official journal of the International Association for the Study of the Liver 16 39605307
2022 Interaction between the PNPLA3 Gene and Nutritional Factors on NAFLD Development: The Korean Genome and Epidemiology Study. Nutrients 16 36615809
2024 PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease. Liver international : official journal of the International Association for the Study of the Liver 15 39559944
2009 Tri-iodothyronine upregulates adiponutrin mRNA expression in rat and human adipocytes. Molecular and cellular endocrinology 15 19619606
2024 The ubiquitin E3 ligase BFAR promotes degradation of PNPLA3. Proceedings of the National Academy of Sciences of the United States of America 14 38294943

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