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J. Biol. Chem., Vol. 279, Issue 26, 27599-27606, June 25, 2004

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Carboxyl Ester Lipase Cofractionates with Scavenger Receptor BI in Hepatocyte Lipid Rafts and Enhances Selective Uptake and Hydrolysis of Cholesteryl Esters from HDL₃^*

Lisa M. Camarota, Jamie M. Chapman, David Y. Hui, and Philip N. Howles

From the Department of Pathology North, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237

Cholesteryl esters are selectively removed from high density lipoproteins by hepatocytes and steroidogenic cells through a process mediated by scavenger receptor BI. In the liver this cholesterol is secreted into bile, primarily as free cholesterol. Previous work showed that carboxyl ester lipase enhanced selective uptake of cholesteryl ether from high density lipoprotein by an unknown mechanism. Experiments were performed to determine whether carboxyl ester lipase plays a role in scavenger receptor BI-mediated selective uptake. When added to cultures of HepG2 cells, carboxyl ester lipase cofractionated with scavenger receptor BI and [³H]cholesteryl ether-labeled high density lipoprotein in lipid raft fractions of cell homogenates. Confocal microscopy of immunostained carboxyl ester lipase and scavenger receptor BI showed a close association of these proteins in HepG2 cells. The enzyme and receptor also cofractionated from homogenates of mouse liver using two different fractionation methods. Antibodies that block scavenger receptor BI function prevented carboxyl ester lipase stimulation of selective uptake in primary hepatocytes from carboxyl ester lipase knockout mice. Heparin blockage of cell-surface proteoglycans also prevented carboxyl ester lipase stimulation of cholesteryl ester uptake by HepG2 cells. Inhibition of carboxyl ester lipase activity in HepG2 cells reduced hydrolysis of high density lipoprotein-cholesteryl esters 40%. In vivo, hydrolysis was similarly reduced in lipid rafts from the livers of carboxyl ester lipase-null mice compared with control animals. Primary hepatocytes from these mice yielded similar results. The data suggest that carboxyl ester lipase plays a physiological role in hepatic selective uptake and metabolism of high density lipoprotein cholesteryl esters by direct and indirect interactions with the scavenger receptor BI pathway.

Received for publication, March 16, 2004 , and in revised form, April 21, 2004.

^* This work was supported by American Heart Association Grant SW-97-16-B and United States Department of Agriculture Grant NRI-2002-01135 (to P. N. H.) and National Institutes of Health Grant R01-HL66246 (to D. Y. H.). 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.

To whom correspondence should be addressed: Dept. of Pathology North-GRI, University of Cincinnati College of Medicine, ML 0507, 2120 E. Galbraith Rd., Cincinnati, OH 45237. Tel.: 513-558-4288; Fax: 513-558-1312; E-mail: philip.howles{at}uc.edu.

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