Fat mass and obesity–associated protein promotes liver steatosis by targeting PPARα

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The fat mass and obesity–associated protein (FTO) has been shown to be involved in obesity; however, its role in NAFLD and the underlying molecular mechanisms remain largely unknown. Methods: FTO expression was first examined in the livers of patients with NAFLD and animal and cellular models of NAFLD by real-time PCR and Western blotting. Next, its role in lipid accumulation in hepatocytes was assessed both in vitro and in vivo via gene overexpression and knockdown studies. Results: FTO expression was obviously elevated in the livers of mice and humans with hepatic steatosis, probably due to its decreased ubiquitination. FTO overexpression in HepG2 cells induced triglyceride accumulation, whereas FTO knockdown exerted an opposing effect. Consistent with the findings of in vitro studies, adeno-associated viruses 8 (AAV8)-mediated FTO overexpression in the liver promoted hepatic steatosis in C57BL/6J mice. Mechanistically, FTO inhibited the mRNA of peroxisome proliferator-activated receptor α (PPARα) in hepatocytes. Activation of PPARα by its agonist GW7647 reversed lipid accumulation in hepatocytes induced by FTO overexpression. Conclusions: Overall, FTO expression is increased in NAFLD, and it promotes hepatic steatosis by targeting PPARα.