Abstract 1586: Ezetimibe Reduces Hepatic Steatosis in Diet-Induced Obese Mice

Ezetimibe is a novel cholesterol absorption inhibitor which reduces plasma LDL-cholesterol by selectively binding to the intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Mice deficient in NPC1L1 are protected from high fat diet-induced fatty liver as well as hypercholesterolemia. The object of this study was to determine whether ezetimibe treatment can reduce hepatic steatosis in diet-induced obese (DIO) mice and to explore the underlying mechanism(s). C57BL/6J mice were fed a high fat/cholesterol diet (Research Diets, with 45% Kcal fat and 0.12% w/w cholesterol) for 7 months after weaning. After 4 weeks, the body weight of DIO mice treated with ezetimibe (5.6 mg/kg/day in the high fat/cholesterol diet) was not significantly different from control mice. However, liver wet weight and the liver to body weight ratio were significantly reduced by 18% in the ezetimibe-treated DIO mice. Livers from ezetimibe-treated mice had significantly lower cholesteryl esters (−84%), free cholesterol (C, −47%) and triglyceride (TG, −20%). After 4 weeks of ezetimibe treatment, total plasma cholesterol and triglyceride was significantly reduced by 30% and 15%, respectively. There were significant decreases in VLDL-C and LDL-C, while HDL-C was not changed in the ezetimibe-treated group. Although the VLDL-C was significantly reduced after ezetimibe treatment, the VLDL-TG production rates were comparable between ezetimibe-treated and control DIO mice. Unlike human liver, mouse liver did not express NPC1L1 under chow or high fat/cholesterol feeding. Microarray analysis demonstrated a significant up-regulation of genes responsible for cholesterol biosynthesis and a modest but significant up-regulation of genes in the citrate cycle and β-oxidation pathway. In conclusion, chronic ezetimibe treatment can significantly reduce hepatic steatosis in mice fed high fat/cholesterol diet by decreasing liver cholesteryl esters, free cholesterol and TG levels, in addition to the reduction of plasma cholesterol and TG levels. Ezetimibe is not only an effective treatment for dyslipidemia, but may also be useful for reducing high fat diet-induced hepatic steatosis.