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J. Biol. Chem., Vol. 280, Issue 46, 38592-38598, November 18, 2005

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Carboxyl Ester Lipase Expression in Macrophages Increases Cholesteryl Ester Accumulation and Promotes Atherosclerosis^*

From the Department of Pathology and Laboratory Medicine, Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237

Carboxyl ester lipase (CEL, also called cholesterol esterase or bile salt-dependent lipase) is a lipolytic enzyme capable of hydrolyzing cholesteryl esters, triacylglycerols, and phospholipids in a trihydroxy bile salt-dependent manner but hydrolyzes ceramides and lysophospholipids via bile salt-independent mechanisms. Although CEL is synthesized predominantly in the pancreas, a low level of CEL expression was reported in human macrophages. This study used transgenic mice with macrophage CEL expression at levels comparable with that observed in human macrophages to explore the functional role and physiological significance of macrophage CEL expression. Peritoneal macrophages from CEL transgenic mice displayed a 4-fold increase in [³H]oleate incorporation into cholesteryl [³H]oleate compared with CEL-negative macrophages when the cells were incubated under basal conditions in vitro. When challenged with acetylated low density lipoprotein, cholesteryl ester accumulation was 2.5-fold higher in macrophages expressing the CEL transgene. The differences in cholesteryl ester accumulation were attributed to the lower levels of ceramide and lysophosphatidylcholine in CEL-expressing cells than in CEL-negative cells. CEL transgenic mice bred to an atherosclerosis susceptible apoE^-/- background displayed an approximate 4-fold higher atherosclerotic lesion area than apoE^-/- mice without the CEL transgene when both were fed a high fat/cholesterol diet. Plasma level of the atherogenic lysophosphatidylcholine was lower in the CEL transgenic mice, but plasma cholesterol level and lipoprotein profile were similar between the two groups. These studies documented that CEL expression in macrophages is pro-atherogenic and that the mechanism is because of its hydrolysis of ceramide and lysophosphatidylcholine in promoting cholesterol esterification and decreasing cholesterol efflux.

Received for publication, February 28, 2005 , and in revised form, September 13, 2005.

^* This work was supported by National Institutes of Health Grant HL66246. 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.

¹ The abbreviations used are: CEL, carboxyl ester lipase; LDL, low density lipoprotein; acLDL, acetylated low density lipoprotein; LTR, long terminal repeat; LPC, lysophosphatidylcholine; ACAT, acyl-CoA:cholesterol acyltransferase; ABCA1, ATP binding cassette transporter A1; apoA-I, apolipoprotein A-I; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

¹ To whom correspondence should be addressed. ML 0507, 2120 E. Galbraith Rd., Cincinnati, OH 45237-0507. Tel.: 513-558-9152; Fax: 513-558-1312; E-mail: huidy{at}email.uc.edu.

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