Abstract 823: Inhibition of Cholesterol Absorption with Ezetimibe Promotes Macrophage to Feces Reverse Cholesterol Transport in Mice
Objectives- The final step in reverse cholesterol transport (RCT) is fecal excretion of peripherally-derived cholesterol as free cholesterol or bile acid. Ezetimibe inhibits the intestinal absorption of cholesterol, and therefore has the potential to promote this step and thus RCT. The aim of these studies was to investigate the effects of ezetimibe on RCT from macrophages to feces.
Methods- Wild type C57BL6/J mice were fed an ezetimibe diet (10mg/kg/day) or a control diet for 2 weeks. In vivo macrophage RCT was assessed by injecting cholesterol loaded and [3H] cholesterol labeled J774 macrophages intraperitoneally into mice and measuring the appearance of 3H-tracer in plasma and feces over 48 hours. In order to specifically determine the effect of ezetimibe on HDL-derived cholesterol, a separate group of mice were injected with HDL labeled with [3H] cholesteryl ether or [3H] cholesteryl oleate, blood was drawn and feces were collected over 48 hours, and liver and small intestine were harvested at 48 hours.
Results- In the macrophage RCT study, ezetimibe treatment did not change the 3H-tracer in plasma; however, there was a 121% increase in the excretion of macrophage-derived 3H-tracer in fecal free sterols with ezetimibe treatment (p<0.01). In the HDL study, there was no change in [3H] cholesteryl ether-HDL or [3H] cholesteryl oleate-HDL fractional catabolic rate or liver and small intestine [3H] cholesteryl ether uptake. However, there was a 94% increase in the fecal excretion of HDL-derived [3H] cholesterol recovered in fecal free sterols after [3H] cholesteryl oleate injection with ezetimibe treatment (p<0.001).
Conclusion- Although ezetimibe does not affect HDL metabolism, it promotes the excretion of macrophage and HDL-derived cholesterol in the feces, indicating that ezetimibe promotes reverse cholesterol transport.