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J. Biol. Chem., Vol. 280, Issue 12, 11876-11886, March 25, 2005

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Modulation of Endosomal Cholesteryl Ester Metabolism by Membrane Cholesterol^*

Yan Wang, Adam B. Castoreno¶, Walter Stockinger, and Axel Nohturfft||

From the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

Cells acquire cholesterol in part by endocytosis of cholesteryl ester containing lipoproteins. In endosomes and lysosomes cholesteryl ester is hydrolyzed by acidic cholesteryl ester hydrolase producing cholesterol and fatty acids. Under certain pathological conditions, however, such as in atherosclerosis, excessive levels of cholesteryl ester accumulate in lysosomes for reasons that are poorly understood. Here, we have studied endosomal and lysosomal cholesteryl ester metabolism in cultured mouse macrophages and with cell-free extracts. We show that net hydrolysis of cholesteryl ester is coupled to the transfer of cholesterol to membranes. When membrane cholesterol levels are low, absorption of cholesterol effectively drives cholesteryl ester hydrolysis. When cholesterol levels in acceptor membranes approach saturation or when cholesterol export is blocked, cholesterol is re-esterified in endosomes. These results reveal a new facet of cellular cholesterol homeostasis and provide a potential explanation for cholesteryl ester accumulation in lysosomes of atherosclerotic cells.

Received for publication, December 30, 2004 , and in revised form, January 14, 2005.

^* This work was supported in part by National Institutes of Health Grant R01 DK59934 (to A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the China Scholarship Council.

These authors contributed equally.

^¶ Supported by a Harvard Graduate School of Arts and Sciences Prize fellowship, the Ford Foundation, and through a Merck-Wiley award.

^|| To whom correspondence should be addressed: The Biological Laboratories, Dept. of Molecular and Cellular Biology, Harvard University, 16 Divinity Ave., Cambridge, MA 02138. Tel.: 617-384-5846; Fax: 617-384-7423; E-mail: axno{at}mcb.harvard.edu.

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