PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date

Introduction An interaction between metabolic triggers and inherited predisposition underpins the development and progression of non alcoholic fatty liver disease (NAFLD) and fatty liver disease in general. Among the specific NAFLD risk variants, PNPLA3 rs738409 C>G, encoding for the p.I148M protein variant, accounts for the largest fraction of liver disease heritability and is being intensively scrutinized. It promotes intrahepatic lipid accumulation and is associated with lipotoxicity and the more severe phenotypes, including fibrosis and carcinogenesis. Therefore, PNPLA3 appears as an appealing therapeutic target to counter NAFLD progression. Areas covered The scope of this review is to briefly describe the PNPLA3 gene and protein function before discussing therapeutic approaches for fatty liver aiming at this target. Literature review was carried out searching through PubMed and clinicaltrials.gov website and focusing on the most recent works and reviews. Expert opinion The main therapeutic strategies under development for NAFLD have shown variable efficacy and side-effects likely due to disease heterogeneity and lack of engagement of the main pathogenic drivers of liver disease. To overcome these limitations, new strategies are becoming available for targeting PNPLA3 p.I148M, responsible for a large fraction of disease susceptibility.

Automated summary

The interaction between metabolic triggers and inherited predisposition plays a crucial role in the development and progression of non-alcoholic fatty liver disease. Among specific NAFLD risk variants, the PNPLA3 rs738409 C>G variant is of significant interest due to its association with lipid accumulation, lipotoxicity, fibrosis, and carcinogenesis. Targeting PNPLA3 p.I148M could be a promising therapeutic approach for NAFLD progression.