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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1745.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Michael E. Greenberg; Jonathan D. Smith; Ephraim Sehayek

From the Institute of Genomic Medicine (M.E.G., E.S.) and the Department of Cell Biology (J.D.S.), Lerner Research Institute, Cleveland Clinic, Ohio.

Correspondence to Ephraim Sehayek, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail sehayee{at}ccf.org

Objective— Human treatment with ezetimibe results in a moderate 50% to 54% decrease in cholesterol absorption and a 15% to 20% decrease in plasma LDL-cholesterol levels; nevertheless, the efficacy of ezetimibe therapy has been recently challenged by the ENHANCE trial. We examined the efficacy of a moderate decrease in cholesterol absorption in preventing atherosclerosis formation in the mouse.

Methods and Results— Congenic 14DKK animals, consisting of a castaneus (CASA/Rk) chromosome 14 interval introgressed onto the C57BL/6J background, displayed a moderate decrease in cholesterol absorption rates. The effect of moderately decreased absorption on atherosclerosis formation was determined in 14DKK apolipoprotein E knockouts (14DKK-apoEKO). When compared to chow diet–fed control apoEKO mice, congenic 14DKK-apoEKO displayed a moderate 41% decrease in cholesterol absorption rates, 30% to 37% decrease in plasma cholesterol levels, and a 70% decrease in atherosclerosis formation. Studies on cholesterol efflux and reverse cholesterol transport (RCT) from 14DKK bone marrow–derived macrophages rejected a 14DKK interval-dependent atheroprotective effects that operate in macrophages. In contrast, 14DKK-apoEKO congenics were characterized by a 60% increase in RCT from peripheral tissue macrophages.

Conclusions— These studies strongly suggest that moderately decreased cholesterol absorption rates result in a large atheroprotective effect attributable to a decrease in plasma cholesterol levels and an increase in RCT from peripheral tissue macrophages.

The atheroprotective effect of moderately decreased cholesterol absorption rates was examined in apolipoprotein E knockout mice. A 41% decrease in cholesterol absorption was associated with a 30% to 37% decrease in plasma cholesterol levels, a 60% increase in RCT, and a 70% decrease in atherosclerosis formation.

Key Words: cholesterol • absorption • atherosclerosis • reverse cholesterol transport • macrophage