JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

• Published in: Journal of pharmacological sciences 2015-07, Vol.128 (3), p.150-157
• Main Authors: Okuma, Chihiro, Ohta, Takeshi, Tadaki, Hironobu, Ishigure, Tatsuya, Sakata, Shohei, Taniuchi, Hideyuki, Sano, Ryuhei, Hamada, Hiromi, Kume, Shinichi, Nishiu, Jun, Kakutani, Makoto
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - metabolism; Acyltransferases - physiology; Animals; Antigens, Bacterial; Bacterial Proteins; de novo lipogenesis; Diglycerides - biosynthesis; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Fatty Acids - biosynthesis; Fatty Liver - metabolism; Fatty Liver - prevention & control; Gene Expression - drug effects; Gene Expression - genetics; Intestinal Absorption - drug effects; JTP-103237; Lipogenesis - drug effects; Lipogenesis - genetics; Liver - metabolism; Male; Mice, Inbred C57BL; Monoacyglycerol acyltransferase; Nonalcoholic fatty liver disease; Piperazines - pharmacology; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Triazoles - pharmacology; Triglycerides - biosynthesis; Triglycerides - metabolism
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2015.06.007

Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.