ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2014
Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 54 citations in OpenAlex.
- LYPLAL1 rare loss-of-function variants in humans and deletion in human hepatoma cells protect against MASLD.Journal of lipid research · 2026Article
- A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD.Antioxidants (Basel, Switzerland) · 2025Article
- Article
- Association of liver fibrosis with extrahepatic cancer in steatotic liver disease patients with PNPLA3 I148M GG genotype.Cancer science · 2024Article
- Comparison of wild-type and high-risk PNPLA3 variants in a human biomimetic liver microphysiology system for metabolic dysfunction-associated steatotic liver disease precision therapy.Frontiers in cell and developmental biology · 2024Article
- PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction.International journal of molecular sciences · 2023Article
- In Vitro Models for the Study of Liver Biology and Diseases: Advances and Limitations.Cellular and molecular gastroenterology and hepatology · 2023Review
- Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC.Biomedicines · 2021Review
- Genetics Is of the Essence to Face NAFLD.Biomedicines · 2021Review
- Quantitative analysis of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells using UHPLC-MS/MS.Journal of separation science · 2021Article
- Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC.International journal of molecular sciences · 2021Review
- Identification of a Metabolic, Transcriptomic, and Molecular Signature of Patatin-Like Phospholipase Domain Containing 3-Mediated Acceleration of Steatohepatitis.Hepatology (Baltimore, Md.) · 2021Article
- Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system.World journal of gastroenterology · 2021Review
- Mechanisms of liver fibrosis and its role in liver cancer.Experimental biology and medicine (Maywood, N.J.) · 2020Review
- Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids.JCI insight · 2019Article
- The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD).Metabolites · 2019Review
- A Case for Not Going Global: "Americanization" of Diet Accelerates Hepatic Mitochondrial Injury in a Model of Wilson Disease.Cellular and molecular gastroenterology and hepatology · 2019Article
- Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity.World journal of gastroenterology · 2018Review
- Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation.Cancer management and research · 2018Review
- Genetic predisposition in nonalcoholic fatty liver disease.Clinical and molecular hepatology · 2017Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
PNPLA3 was recently associated with the susceptibility to nonalcoholic fatty liver disease, a common cause of chronic liver disease characterized by abnormal triglyceride accumulation. Although it is established that PNPLA3 has both triacylglycerol lipase and acylglycerol O-acyltransferase activities, is still unknown whether the gene has any additional role in the modulation of the human liver metabolome. To uncover the functional role of PNPLA3 on liver metabolism, we performed high-throughput metabolic profiling of PNPLA3 siRNA-silencing and overexpression of wild-type and mutant Ile148Met variants (isoleucine/methionine substitution at codon 148) in Huh-7 cells. Metabolomic analysis was performed by using GC/MS and LC/MS platforms. Silencing of PNPLA3 was associated with a global perturbation of Huh-7 hepatoma cells that resembled a catabolic response associated with protein breakdown. A significant decrease in amino- and γ-glutamyl-amino acids and dipeptides and a significant increase in cysteine sulfinic acid, myo-inositol, lysolipids, sphingolipids, and polyunsaturated fatty acids were observed. Overexpression of the PNPLA3 Met148 variant mirrored many of the metabolic changes observed during gene silencing, but in the opposite direction. These findings were replicated by the exploration of canonical pathways associated with PNPLA3 silencing and Met148 overexpression. Overexpression of the PNPLA3 Met148 variant was associated with a 1.75-fold increase in lactic acid, suggesting a shift to anaerobic metabolism and mitochondrial dysfunction. Together, these results suggest a critical role of PNPLA3 in the modulation of liver metabolism beyond its classical participation in triacylglycerol remodeling.
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