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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1144.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

Epoxycholesterol Impairs Cholesteryl Ester Hydrolysis in Macrophage Foam Cells, Resulting in Decreased Cholesterol Efflux

Mireille Ouimet; Ming-Dong Wang; Natalie Cadotte; Kenneth Ho; Yves L. Marcel

From the Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, and Departments of Biochemistry, Microbiology, and Immunology, and Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada.

Correspondence to Y.L. Marcel, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. E-mail ylmarcel{at}ottawaheart.ca

Objective— Strategies to inhibit or reverse cholesterol accumulation in macrophages have been shown to be atheroprotective. Notably, the administration of LXR agonists upregulates key players in the reverse cholesterol transport pathway, including the ABCA1 and ABCG1 transporters. However, the effects of natural LXR activators, oxysterols, on lipid-laden macrophages remains elusive.

Methods and Results— We assessed the ability of 2 oxysterols, 22(R)-hydroxycholesterol (22-OH) and 24(S),25-epoxycholesterol (epoxycholesterol), to promote cholesterol efflux to apoA-I from LDL- and modified LDL-labeled and loaded macrophages and thus rescue the phenotype associated with the accumulation of cellular cholesterol in these cells. In macrophages labeled with LDL-derived cholesterol, epoxycholesterol treatment enhances ABCA1-mediated cholesterol efflux. In contrast, in AcLDL-loaded macrophages, epoxycholesterol treatment decreases cholesterol efflux to apoA-I, despite a dramatic increase in the expression of ABCA1 in response to epoxycholesterol treatment. We show that the decreased efflux is attributable to impaired cholesterol mobilization from lipid droplets, resulting from decreased cholesteryl ester hydrolase activity.

Conclusion— Epoxycholesterol impairs cholesteryl ester hydrolysis activity in macrophage foam cells, thus reducing the availability of cholesterol for efflux to cholesterol acceptors.

We report that in cholesterol-loaded macrophages, epoxycholesterol decreases ABCA1- and ABCG1-mediated cholesterol efflux, despite increasing the expression of both transporters. We show that epoxycholesterol impairs cholesteryl ester hydrolysis activity in macrophage foam cells, thus reducing the availability of cholesterol for efflux to apoA-I and HDL.

Key Words: macrophage • epoxycholesterol • cholesteryl ester hydrolysis • cholesterol • ABCA1

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