JTT-130,a novel intestine-specific inhibitor of microsomal triglyceride transfer protein,ameliorates lipid metabolism and attenuates atherosclerosis in hyperlipidemic animal models

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. © 2015 the authors. production and hosting by elsevier b.v.