Acyl-coenzyme A: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, Douglas Thewke

    Research output: Contribution to journalArticle

    29 Scopus citations

    Abstract

    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 (cPLA 2). 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 P388B1 cells. The decrease in 7KC ester accumulation produced by the inhibition of cPLA 2 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.

    Original languageEnglish (US)
    Pages (from-to)1933-1943
    Number of pages11
    JournalJournal of lipid research
    Volume46
    Issue number9
    DOIs
    StatePublished - Sep 2005

    Keywords

    • 7-ketocholesterol
    • Low density lipoproteins
    • Oxysterol esterification

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology
    • Cell Biology

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