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A more recent version of this article appeared on March 25, 2005
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M414676200v1
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Papers In Press, published online ahead of print January 18, 2005
J. Biol. Chem, 10.1074/jbc.M414676200
Submitted on December 30, 2004
Revised on January 14, 2005
Accepted on January 14, 2005

Modulation of endosomal cholesteryl ester metabolism by membrane cholesterol

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

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

Corresponding Author: axno{at}mcb.harvard.edu

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.


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