PROTECTIVE EFFECT OF FTO ABLATION AGAINST PALMITIC ACID-INDUCED LIPOTOXICITY IN NASH

Abstract

Genome-wide association studies (GWAS) have identified noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene to be strongly associated with effects on food intake and adiposity in humans. However, its causative role in obesity related metabolic disorders remain unclear. Non-alcoholic steatohepatitis (NASH) is a common comorbidity associated with obesity, and is characterized with excess fat accumulation and increased lipotoxicity in hepatocytes. In this work, investigations into the role of FTO in NASH were undertaken. Hepatic FTO expression is significantly increased in both NASH patients and rodent model of NASH. Furthermore, genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER-stress, and apoptosis in vitro. Taken together, these results strongly suggest that the upregulation of FTO may lead to increased liver damage in NASH, and its pharmacological modulation may represent a novel strategy to counter hepatic lipotoxicity.