Mo1991 Sitagliptin Inhibits the Development of Hepatic Steatosis by Down-Regulated Expressions of Hepatic Acetyl-CoA Carboxyrase (ACC) and Fatty Acid Synthase (Fas)

Abstract

Aims; Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key factor of obesity-related metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. Although sitagliptin (dipeptidyl peptidase-4 inhibitior) is a treatment drug used for type 2 diabetic mellitus (T2DM) patients, the role of sitagliptin in the development NAFLD has not yet been well known. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis. We investigated whether the treatment of sitagliptin is metabolically connected to hepatic steatosis. Methods: Five-week-old male ob/ob mice, which develop T2DM and NAFLD by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks (Control group; n=6) as controls, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks (Sitagliptin group; n=6). Results: Histological comparison between the liver of Control group and that of Sitagliptin group showed significantly more inhibition of hepatic steatosis than in Sitagliptin group. It was suggested that sitagliptin inhibited the development of hepatic steatosis in the mice induced by histologically. The enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) regulate the synthesis of fatty acids. Sitagliptin reduced the hepatic expressions of ACC and FAS, markedly inhibited hepatic de novo lipogenesis, and protected against hepatic steatosis in ob/ob mice. Conclusion: These findings suggested that sitagliptin has effects of downregulated hepatic ACC and FAS in lipid metabolism. Therefore, sitagliptin may serve as a potential target to treat NAFLD and T2DM.