ArticleProceedings of the National Academy of Sciences of the United States of America2019
Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers, 2 of them syntheses that pooled it.
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Who cites it
173 citing papers in PubMed, 2 syntheses or guidelines pooled it, 276 citations in OpenAlex.
- Efficacy of different interventions for nonalcoholic fatty liver disease: A meta-analysis of lifestyle modifications, silymarin, and medications.Asia Pacific journal of clinical nutrition · 2025Pooled it
- Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.Nature genetics · 2023Pooled it
- Lipodystrophy and adipose tissue recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.The Journal of pathology · 2026Article
- The Emerging Challenge of Non-Cirrhotic MASLD-Related Hepatocellular Carcinoma: Etiology, Immunopathology, and Precision Oncology.Liver cancer · 2026Review
- Review
- Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and environmental challenges.Journal of hepatology · 2026Article
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.Nature cell biology · 2026Article
- The benchmarking and application of tag-degraders in vivo to validate therapeutic targets.Nature communications · 2026Article
- PNPLA3-I148M reduces hepatic triacylglycerol secretion and mitigates diet induced left ventricular diastolic dysfunction.Scientific reports · 2026Article
- MAFLD: a ferroptotic disease.Trends in molecular medicine · 2026Review
- Multiscale Analysis of PNPLA2 and PNPLA3 Membrane Targeting.bioRxiv : the preprint server for biology · 2026Article
- Understanding Liver and Digestive Diseases: A Paved Road to Improve Diagnosis, Management, and Treatment.Exploration of digestive diseases · 2026Article
- Rewriting the MASLD-associated hepatocellular carcinoma script: Targeting epigenetics and metabolism.International journal of cancer · 2025Review
- Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress.bioRxiv : the preprint server for biology · 2025Article
- A genetic map of human metabolism across the allele frequency spectrum.Nature genetics · 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
- [Research progress on clinical characteristics and pathological mechanisms of lean metabolic-associated fatty liver disease].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Review
- Adding salt to foods increases the risk of metabolic dysfunction-associated steatotic liver disease.Communications medicine · 2025Article
- Genetic variants influencing liver fat in normal-weight individuals of European ancestry.JHEP reports : innovation in hepatology · 2025Article
113 more citing papers are in PubMed but not listed here.
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5 authors at 1 institution in 1 country.
Funding
Abstract
Fatty liver disease (FLD) is a disorder in which accumulation of triglycerides (TGs) in the liver can lead to inflammation, fibrosis, and cirrhosis. Previously, we identified a variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) that is strongly associated with FLD, but the mechanistic basis for the association remains elusive. Although PNPLA3 has TG hydrolase activity in vitro, inactivation or overexpression of the WT protein in mice does not cause steatosis. In contrast, expression of two catalytically defective forms of PNPLA3 (I148M or S47A) in sucrose-fed mice causes accumulation of both PNPLA3 and TGs on hepatic lipid droplets (LDs). To determine if amassing PNPLA3 on LDs is a cause or consequence of steatosis, we engineered a synthetic isoform of PNPLA3 that uncouples protein accumulation from loss of enzymatic activity. Expression of a ubiquitylation-resistant form of PNPLA3 in mice caused accumulation of PNPLA3 on hepatic LDs and development of FLD. Lowering PNPLA3 levels by either shRNA knockdown or proteolysis-targeting chimera (PROTAC)-mediated degradation reduced liver TG content in mice overexpressing PNPLA3(148M). Taken together, our results show that the steatosis associated with PNPLA3(148M) is caused by accumulation of PNPLA3 on LDs.
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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.