Abstract 1184: Hdl Protects Macrophages From Oxidized Ldl-induced Apoptosis By Promoting Efflux Of 7-ketocholesterol Via Abcg1

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Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to HDL. We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL (oxLDL). The protective effect of HDL was reduced in Abcg1 −/− macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxLDL and atherosclerotic lesions, in Abcg1 +/+ but not in Abcg1 −/− macrophages. In transfected 293 cells, efflux of 7-ketocholesterol was completely dependent on expression of ABCG1 and presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate efflux of 7-ketocholesterol into media. HDL stimulated efflux of 7-ketocholesterol from Abcg1 +/+ but not from Abcg1 −/− macrophages, and Abcg1 −/− macrophages accumulated 7-ketocholesterol in mice fed the Western diet. The findings indicate a specific role of ABCG1 in promoting efflux of 7-ketocholesterol from macrophages onto HDL, and in protecting these cells from oxysterol-induced toxicity.