title: JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: Chihiro.okuma@jt.com.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Okuma
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Tadaki
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishigure
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Taniuchi
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Sano
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kume
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nishiu
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kakutani
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004075:Diglycerides / Q000096:biosynthesis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis*; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007408:Intestinal Absorption / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C000606936:7-(4,6-di-tert-butylpyrimidin-2-yl)-3-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro(1,2,4)triazolo(4,3-a)pyrazine; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004075:Diglycerides; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010879:Piperazines; D051780:Sterol Regulatory Element Binding Protein 1; D014230:Triazoles; D014280:Triglycerides; C093537:invJ protein, Salmonella typhimurium; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: JTP-103237; Monoacyglycerol acyltransferase; Nonalcoholic fatty liver disease; de novo lipogenesis