title: JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates lipid metabolism and attenuates atherosclerosis in hyperlipidemic animal models.
abstract: JTT-130 was developed as an intestine-specific MTP inhibitor designed to rapidly catabolize after absorption to avoid causing hepatotoxicity due to hepatic MTP inhibition. In previous reports, we have demonstrated that JTT-130 suppresses dietary lipid absorption in the small intestine without inducing hepatic steatosis. Thus, in this report, JTT-130 was administered to hyperlipidemic animals fed a Western diet to investigate the effect of intestinal MTP inhibition on lipid metabolism and progression of atherosclerosis. JTT-130 potently lowered plasma non-high density lipoprotein-cholesterol, and elevated plasma high density lipoprotein-cholesterol (HDL-C), indicating improvement in atherogenic index in hamsters. HDL fractions obtained after two weeks treatment with JTT-130 significantly increased the efflux of cholesterol from macrophages, as an index parameter of HDL function. Furthermore, long-term treatment with JTT-130 also improved the plasma lipid profile without inducing hepatic steatosis in rabbits, resulting in the suppression of atherosclerosis formation in aortas. From these results, JTT-130 ameliorates lipid metabolism accompanied with the enhancement of the anti-atherosclerotic function of HDL, and attenuates the progression of atherosclerosis in hyperlipidemic animals. These findings indicate that intestinal MTP inhibition may be atherogenic in vivo and that JTT-130 may be a useful compound for the treatment of dyslipidemia and a potential anti-atherogenic drug.
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: yasuko.mera@jt.com.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mera
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Odani
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sasase
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Miyajima
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: Makoto
authors.initials: M
authors.lastname: Kakutani
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000378:metabolism; D006224:Cricetinae; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008314:Malonates / Q000008:administration & dosage* / Q000494:pharmacology*; D008647:Mesocricetus; D011817:Rabbits
chemical_list: D001549:Benzamides; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D008314:Malonates; C556241:diethyl 2-((3-dimethylcarbamoyl-4-((4'-trifluoromethylbiphenyl-2-carbonyl)amino)phenyl)acetyloxymethyl)-2-phenylmalonate; C106092:microsomal triglyceride transfer protein
keywords: Atherosclerosis; Dyslipidemia; HDL function; JTT-130; Microsomal triglyceride transfer protein