ArticleHepatology (Baltimore, Md.)2019
PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice.
Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
122 citing papers in PubMed, 2 syntheses or guidelines pooled it, 210 citations in OpenAlex.
- Meta-Analysis: Effects of Steatotic Liver Disease-Associated Genetic Risk Alleles on Longitudinal Outcomes.Alimentary pharmacology & therapeutics · 2025Pooled it
- Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.Nature genetics · 2023Pooled it
- A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.The Journal of nutrition · 2020Trial
- Article
- Molecular mechanisms and pathogenesis of MASH.Nature · 2026Review
- Precision pathophysiology in steatotic liver disease.Clinical and molecular hepatology · 2026Review
- Autophagy in MASLD: A Metabolic and Precision Medicine Perspective.Liver international : official journal of the International Association for the Study of the Liver · 2026Review
- Replication of acne susceptibility loci and gene-environment interactions with screen time in Singapore and Malaysia Chinese population.JID innovations : skin science from molecules to population health · 2026Article
- PNPLA3-I148M reduces hepatic triacylglycerol secretion and mitigates diet induced left ventricular diastolic dysfunction.Scientific reports · 2026Article
- Mechanisms and therapeutic insights into MASH-associated fibrosis.Trends in endocrinology and metabolism: TEM · 2026Review
- PNPLA3 I148M is unrelated to HCC occurrence but associates with poorer tumor differentiation in Korean MASLD: a prospective cohort of 562 patients.Journal of liver cancer · 2026Article
- A Global Perspective on Metabolic Dysfunction-Associated Steatotic Liver Disease: From Molecular Mechanisms to Therapeutic Strategy Innovation.Nutrients · 2026Review
- The I148M PNPLA3 Variant Forces Progressive Portal MASLD by Spatially Perturbing Metabolic Pathways Across Liver Zones.International journal of molecular sciences · 2026Article
- Patatin-domain-containing (phospho)lipases under control: Mammalian co-regulators and pathogenic activation mechanisms.FEBS open bio · 2026Review
- The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice.The American journal of pathology · 2026Article
- Primary Human Tissue Models for Metabolic Dysfunction-Associated Liver Disease - toward Streamlining Drug Discovery with Patient-Derived Assays.Advanced biology · 2025Review
- Chrysanthemum morifolium extract improves metabolic dysfunction-associated fatty liver disease by regulating lipid metabolism.Scientific reports · 2025Article
- Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress.bioRxiv : the preprint server for biology · 2025Article
- The pathogenesis of hepatic steatosis in MASLD: a lipid droplet perspective.The Journal of clinical investigation · 2025Article
- Fifteen Years of PNPLA3: Transforming Hepatology Through Human Genetics.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
62 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
A variant (148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a major risk factor for fatty liver disease. Despite its clinical importance, the pathogenic mechanism linking the variant to liver disease remains poorly defined. Previously, we showed that PNPLA3(148M) accumulates to high levels on hepatic lipid droplets (LDs). Here we examined the effect of that accumulation on triglyceride (TG) hydrolysis by adipose triglyceride lipase (ATGL), the major lipase in the liver. As expected, overexpression of ATGL in cultured hepatoma (HuH-7) cells depleted the cells of LDs, but unexpectedly, co-expression of PNPLA3(wild type [WT] or 148M) with ATGL inhibited that depletion. The inhibitory effect of PNPLA3 was not caused by the displacement of ATGL from LDs. We tested the hypothesis that PNPLA3 interferes with ATGL activity by interacting with its cofactor, comparative gene identification-58 (CGI-58). Evidence supporting such an interaction came from two findings. First, co-expression of PNPLA3 and CGI-58 resulted in LD depletion in cultured cells, but expression of PNPLA3 alone did not. Second, PNPLA3 failed to localize to hepatic LDs in liver-specific Cgi-58 knockout (KO) mice. Moreover, overexpression of PNPLA3(148M) increased hepatic TG levels in WT, but not in Cgi-58 KO mice. Thus, the pro-steatotic effects of PNPLA3 required the presence of CGI-58. Co-immunoprecipitation and pulldown experiments in livers of mice and in vitro using purified proteins provided evidence that PNPLA3 and CGI-58 can interact directly. Conclusion: Taken together, these findings are consistent with a model in which PNPLA3(148M) promotes steatosis by CGI-58-dependent inhibition of ATGL on LDs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.