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Journal of Lipid Research, Vol. 44, 1676-1685, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Oxidized LDL activates phospholipase A₂ to supply fatty acids required for cholesterol esterification

Satoshi Akiba¹, Yukimasa Yoneda, Satoshi Ohno, Megumi Nemoto and Takashi Sato

Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan

¹ To whom correspondence should be addressed. e-mail: akiba{at}mb.kyoto-phu.ac.jp

We examined the roles of phospholipase A₂ (PLA₂) in oxidized LDL (oxLDL)-induced cholesteryl ester formation in macrophages. In [³H]oleic acid-labeled RAW264.7 cells and mouse peritoneal macrophages, oxLDL induced [³H]cholesteryl oleate formation with an increase in free [³H]oleic acid and a decrease in [³H]phosphatidylcholine. The changes in these lipids were suppressed by methyl arachidonyl fluorophosphonate (MAFP), a cytosolic PLA₂ (cPLA₂) inhibitor. However, MAFP had no effect on the ACAT activity or the binding and/or uptake of oxLDL. Stimulation with oxLDL in the presence of [³H]cholesterol increased [³H]cholesteryl ester bearing fatty acyl chains derived from cellular and/or exogenous (oxLDL) lipids. The formation of cholesteryl ester under this condition was also inhibited by MAFP, and the inhibitory effect was reversed by adding oleic acid. While oxLDL did not affect the activity or amounts of cPLA₂, preincubation with oxLDL enhanced the release of oleic acid and arachidonic acid induced by ionomycin in RAW264.7 cells. 13(S)-hydroxyoctadecadienoic acid, but not 7-ketocholesterol, also enhanced ionomycin-induced oleic acid release.

These results suggest that oxLDL induces cPLA₂ activation, which contributes, at least in part, to the supply of fatty acids required for the cholesteryl esterification, probably through the acceleration by oxidized lipids of the catalytic action of cPLA₂ in macrophages.

Abbreviations: cPLA₂, cytosolic PLA₂; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetra-methylindocarbocyanine; 13-HODE, 13(S)-hydroxyoctadecadienoic acid; iPLA₂, Ca²⁺-independent cytosolic PLA₂; MAFP, methyl arachidonyl fluorophosphonate; oxLDL, oxidized LDL; PLA₂, phospholipase A₂; TBARS, thiobarbituric acid-reactive substances

Supplementary key words cholesteryl ester • cytosolic phospholipase A₂ • foam cell • hydroxyoctadecadienoic acid • macrophage

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