Abstract 11008: Ezetimibe Enhances Macrophage Reverse Cholesterol Transport in Hamsters Independent of Transintestinal Cholesterol Efflux Pathway
Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. RCT from macrophages (macrophage RCT) is a critical mechanism of anti-atherogenecity of high-density lipoproteins (HDL). An inhibitor of cholesterol absorption, ezetimibe, reportedly promotes macrophage RCT in mice lacking cholesterol ester transfer protein (CETP); we therefore investigated it in hamsters.
As shown in Figures, high-cholesterol diet (HCD) increased cholesterol levels in overall lipoprotein fractions (very low-density/low-density lipoproteins, VLDL/LDL/HDL). Ezetimibe markedly reduced VLDL/LDL cholesterol levels under both normal chow (NC) and HCD; however, did not affect under NC and rather reduced HDL-cholesterol levels under HCD. Macrophage RCT assay revealed that HCD increased hepatic levels of 3H-cholesterol derived from pre-labeled macrophages intraperitoneally injected; in contrast, HCD reduced it in bile, both of which were completely cancelled by ezetimibe. Despite reduced tracer levels in liver, ezetimibe enhanced fecal excretion of 3H-sterol under both NC and HCD, indicating that ezetimibe promoted RCT in vivo. Finally, to further test whether a transintestinal cholesterol efflux (TICE) pathway contributes to the enhanced RCT, we performed macrophage RCT assay using the hamsters whose bile duct was ligated. Bile duct ligation markedly inhibited macrophage-derived 3H-cholesterol excretion to feces and cancelled the stimulatory effect of ezetimibe on RCT, suggesting that TICE minimally contributed to RCT thus ezetimibe did not directly act on intestine, but promoted cholesterol excretion to the bile.
In conclusion, ezetimibe exerts an additive anti-atherogenic property by enhancing RCT in CETP-expressing animals, hamster. Our data also suggest that such effect of ezetimibe is independent of the TICE pathway.
- © 2013 by American Heart Association, Inc.