J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500101-JLR200 on July 1, 2005

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Journal of Lipid Research, Vol. 46, 1933-1943, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages

Natalie E. Freeman*, Antonio E. Rusinol*, MacRae Linton{dagger}, David L. Hachey§, Sergio Fazio{dagger}, Michael S. Sinensky* and Douglas Thewke1,*

* Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0581
{dagger} Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300
§ Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN 37232-8575

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500101-JLR200

1 To whom correspondence should be addressed. e-mail: thewke{at}etsu.edu

7-Ketocholesterol (7KC) is a cytotoxic component of oxidized low density lipoproteins (OxLDLs) and induces apoptosis in macrophages by a mechanism involving the activation of cytosolic phospholipase A2 (cPLA2). In the current study, we examined the role of 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, compared with 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 the inhibition of cPLA2 was reversed by supplementing with either oleic or arachidonic acid (AA); however, only AA supplementation restored the induction of apoptosis by 7KC.

These results suggest that 7KC not only initiates the apoptosis pathway by activating cPLA2, as we have reported previously, but also participates in the downstream signaling pathway when esterified by ACAT to form 7KC-arachidonate.

Abbreviations: AA, arachidonic acid; AACOCF3, arachidonyl trifluoromethyl ketone; ACAT, acyl-coenzyme A:cholesterol acyltransferase; cPLA2, cytosolic phospholipase A2; ETYA, 5,8,11,14-eicosatetraynoic acid; MPM, mouse peritoneal macrophage; OxLDL, oxidized low density lipoprotein; TUNEL, terminal transferase-mediated dUTP nick end labeling; 7KC, 7-ketocholesterol; 7KC ester, 7-ketocholesteryl ester; 25-OHC, 25-hydroxycholesterol

Supplementary key words 7-ketocholesterol • oxysterol esterification • low density lipoproteins


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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.