Rosuvastatin activates ATP-binding cassette transporter A1-dependent efflux ex vivo and promotes reverse cholesterol transport in macrophage cells in mice fed a high-fat diet

Abstract

Objective - It is controversial whether statins improve high-density lipoprotein (HDL) function, which plays an important role in reverse cholesterol transport in vivo. The aim of the present study was to clarify the effects of rosuvastatin and atorvastatin on reverse cholesterol transport in macrophage cells in vivo and their underlying mechanisms. Approach and Results - Male C57BL mice were divided into 3 groups (rosuvastatin, atorvastatin, and control groups) and orally administered rosuvastatin, atorvastatin, or placebo for 6 weeks under feeding with a 0.5% cholesterol+10% coconut oil diet. After administration, although there were no changes in plasma HDL cholesterol levels among the groups, plasma from the rosuvastatin group showed an increased ability to promote ATP-binding cassette transporter A1- mediated cholesterol efflux ex vivo. In addition, capillary electrophoresis revealed a shift in HDL toward the pre-β HDL fraction only in the rosuvastatin group. Mice in all 3 groups were intraperitoneally injected with 3H-cholesterol-labeled and cholesterol-loaded macrophages and then were monitored for the appearance of 3H-tracer in plasma and feces. The amount of 3H-tracer excreted into feces during 48 hours in the rosuvastatin group was greater than that in the control group. Finally, 3H-cholesteryl oleate-HDL was intravenously injected into all groups, blood samples were taken, and the count of 3H-cholesterol was analyzed. Plasma 3H-cholesteryl oleate-HDL changed similarly, and no differences in fractional catabolic rates were observed. Conclusions - Rosuvastatin enhanced the ATP-binding cassette transporter A1-dependent HDL efflux function of reverse cholesterol transport, and this finding highlights the potential of rosuvastatin for the regression of atherosclerosis.