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A more recent version of this article appeared on September 1, 2005

Papers In Press, published online ahead of print July 1, 2005
J. Lipid Res., doi:10.1194/jlr.M500101-JLR200
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Submitted on March 17, 2005
Revised on June 7, 2005
Accepted on June 22, 2005

Acyl-CoA: Cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages

Natalie E. Freeman, Antonio E. Rusinol, MacRae Linton, David L. Hachey, Sergio Fazio, Michael S. Sinensky, and Douglas P. Thewke

Biochemistry & Molecular Biology, East Tennessee State University, Johnson City, TN 37614

Corresponding Author: thewke{at}etsu.edu

7-ketocholesterol (7KC) is a cytotoxic component of oxidized low-density lipoproteins (oxLDL) and induces apoptosis in macrophages by a mechanism involving activation of cytosolic phospholipase A2 (cPLA2). In the current study, we examined the role of acyl-CoA: cholesterol acyltransferase (ACAT) in 7KC-induced and oxLDL-induced apoptosis in murine macrophages. An ACAT inhibitor, Sandoz 58-035, suppressed 7KC-induced apoptosis in P388D1 cells and both 7KC-induced and oxLDL-induced apoptosis in mouse peritoneal macrophages (MPMs). Furthermore, in comparison to wild type MPMs, ACAT-1 deficient MPMs demonstrated significant resistance to both 7KC-induced and oxLDL-induced apoptosis. Macrophages treated with 7KC accumulated ACAT-derived [14C]cholesteryl and [3H]7-ketocholesteryl esters. Tandem LC/MS revealed that the 7KC esters contained primarily saturated and monounsaturated fatty acids. An inhibitor of cPLA2, arachidonyl trifluoromethyl ketone, prevented the accumulation of 7KC esters and inhibited 7KC-induced apoptosis in P388D1 cells. The decrease in 7KC ester accumulation produced by inhibition of cPLA2 was reversed by supplementing with either oleic or arachidonic acid; however, only arachidonic acid supplementation restored induction of apoptosis by 7KC. These results suggest that 7KC not only initiates the apoptosis pathway by activating cPLA2, as we have previously reported, but also participates in the downstream signaling pathway when esterified by ACAT to form 7KC-arachidonate.


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