Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.
Keywords: PNPLA3; alcoholic liver disease; cirrhosis; fibrosis; hepatocellular carcinoma; nonalcoholic steatohepatitis; rs738409.
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PNPLA3 I148M Variant Influences Circulating Retinol in Adults With Nonalcoholic Fatty Liver Disease or ObesityA Mondul et al. J Nutr 145 (8), 1687-91. PMID 26136587.We showed for the first time, to our knowledge, that carriers of the PNPLA3 148M allele with either fatty liver plus obesity or obesity alone have lower fasting circulati …
PNPLA3 rs738409 Underlies Treatment Response in Nonalcoholic Fatty Liver DiseaseJZ Wang et al. World J Clin Cases 6 (8), 167-175. PMID 30148144. - ReviewNon-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domai …
The rs2294918 E434K Variant Modulates Patatin-Like Phospholipase Domain-Containing 3 Expression and Liver DamageB Donati et al. Hepatology 63 (3), 787-98. PMID 26605757.Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I14 …
Patatin-like Phospholipase Domain containing-3 Gene I148M Polymorphism, Steatosis, and Liver Damage in Hereditary HemochromatosisL Valenti et al. World J Gastroenterol 18 (22), 2813-20. PMID 22719190.The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.
PNPLA3 Gene in Liver DiseasesE Trépo et al. J Hepatol 65 (2), 399-412. PMID 27038645. - ReviewGenome-wide association studies (GWAS) in the field of liver diseases have revealed previously unknown pathogenic loci and generated new biological hypotheses. In 2008, a …