Abstract
Nonalcoholic fatty liver disease (NAFLD) is highly correlated with obesity, and lifestyle changes to reduce weight remain the main therapeutic approach. The noncoding RNA miR-22 has previously been reported to be highly abundant in the sera of NAFLD patients. In addition, miR-22 directly targets peroxisome proliferative-activated receptor, Pgc-1α, peroxisome proliferator-activated receptor α, and sirtuin 1 (Sirt1), which are important factors involved in fatty acid metabolism. Given that miR-22 directly targets genes involved in the control of metabolism and obesity, we investigated whether miR-22 contributes to metabolic alterations induced by obesity. We observed increased expression of miR-22, decreased expression of Sirt1, and alterations in the expression of adipogenesis-related genes in a mouse model of obesity and a human hepatocyte cell line. We identified that miR-22 and the 3'-UTR of Sirt1 are complementary. Mutation of the complementary fragment abolishes the ability of miR-22 to regulate the Sirt1 gene. Furthermore, treatment of hepatic steatosis cells with miR-22 mimics or inhibitors showed that miR-22 can promote hepatic steatosis, and miR-22 inhibitors effectively reduced triglyceride levels without affecting cell activity. Finally, we validated that miR-22 has similar effects on downstream lipid metabolism-related genes. Our data reveal the pathways and mechanisms through which miR-22 regulates lipid metabolism and suggest that miR-22 inhibitors may have potential as candidate drugs for NAFLD and obesity.