Ezetimibe Enhances Macrophage-to-Feces Reverse Cholesterol Transport in Golden Syrian Hamsters Fed a High-Cholesterol Diet

Abstract

The aim of this work was to evaluate reverse cholesterol transport (RCT) in hamster, animal model expressing CETP under a high cholesterol diet (HF) supplemented with Ezetimibe using primary labelled macrophages. We studied three groups of hamsters (n=8/group) for 4 weeks: 1) chow diet group: Chow, 2) High cholesterol diet group: HF and 3) HF group supplemented with 0.01% of ezetimibe: HF+0.01%Ezet. Following intraperitoneal injection of ³H-cholesterol-labelled hamster primary macrophages, we measured the in vivo macrophage-to-feces RCT. .HF group exhibited an increase of triglycerides (TG), cholesterol, glucose in plasma and higher TG and cholesterol content in liver (p<0.01) compared to Chow group. Ezetimibe induced a significant decrease in plasma cholesterol with a lower LDL and VLDL cholesterol (p<0.001) and in liver cholesterol (p<0.001) and TG (p<0.01) content compared to HF. In vivo RCT essay showed an increase of tracer level in plasma and liver (p<0.05) but not in feces in HF compared to Chow group. The amount of labelled total sterol and cholesterol in liver and feces was significantly reduced (p<0.05) and increased (p=0.05) respectively with Ezetimibe treatment. No significant increase was obtained for labelled feces bile acids in HF+0.01%Ezet compared to HF. Ezetimibe decreased SCD1 gene expression and increased SR-B1 (p<0.05) in liver but did not affect NPC1L1 nor ABCG5 and ABCG8 expression in jejunum. In conclusion, ezetimibe exhibited an atheroprotective effect by enhancing RCT in hamster and decreasing LDL cholesterol. Ours findings showed also a hepatoprotective effect of ezetimibe by decreasing hepatic fat content. Significance Statement This work was assessed to determine the effect of ezetimibe treatment on high cholesterol diet induced disturbances and especially the effect on reverse cholesterol transport in animal model with CETP activity and using labelled primary hamster macrophages. We were able to demonstrate that ezetimibe exhibited an atheroprotective effect by enhancing RCT and by decreasing LDL cholesterol in hamster. We showed also a hepatoprotective effect of ezetimibe by decreasing hepatic fat content.

Keywords: Liver; cholesterol; cholesterol metabolism/lipoproteins; intestinal transport; lipoproteins.