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: Yasuko Mera, Takashi Kawai, Naoto Ogawa, Naoya Odani, Tomohiko Sasase, Katsuhiro Miyajima, Takeshi Ohta, Makoto Kakutani
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 129 Issue 3 Pg. 169-76 (Nov 2015) ISSN: 1347-8648 [Electronic] Japan
• PMID: 26598005 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• Carrier Proteins
• Cholesterol, HDL
• Malonates
• diethyl 2-((3-dimethylcarbamoyl-4-((4'-trifluoromethylbiphenyl-2-carbonyl)amino)phenyl)acetyloxymethyl)-2-phenylmalonate
• microsomal triglyceride transfer protein

Topics

• Animals
• Atherosclerosis (drug therapy, etiology, metabolism, prevention & control)
• Benzamides (administration & dosage, pharmacology)
• Carrier Proteins (antagonists & inhibitors)
• Cholesterol, HDL (metabolism)
• Cricetinae
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Disease Progression
• Hyperlipidemias (drug therapy, etiology, metabolism, prevention & control)
• Intestinal Mucosa (metabolism)
• Lipid Metabolism (drug effects)
• Male
• Malonates (administration & dosage, pharmacology)
• Mesocricetus
• Rabbits