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High-Density Lipoprotein Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Apoptosis by Promoting Efflux of 7-Ketocholesterol via ABCG1

Naoki Terasaka, Nan Wang, Laurent Yvan-Charvet and Alan R. Tall
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 38 (Sep. 18, 2007), pp. 15093-15098
Stable URL: http://www.jstor.org/stable/25449089
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
High-Density Lipoprotein Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Apoptosis by Promoting Efflux of 7-Ketocholesterol via ABCG1
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Abstract

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 high-denisty lipoprotein (HDL). We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL. 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 oxidized LDL and atherosclerotic lesions, in $Abcg1^{+/+}$, but not in $Abcg1^{-/-}$ macrophages. In transfected 293 cells, efflux of 7-ketocholesterol and related oxysterols was completely dependent on expression of ABCG1 and the presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate the efflux of 7-ketocholesterol into media. HDL stimulated the efflux of 7-ketocholesterol from $Abcg1^{+/+}$, but not from $Abcg1^{-/-}$ macrophages. In $Abcg1^{-/-}$ mice fed a high-cholesterol diet, plasma levels of 7-ketocholesterol were reduced, whereas their macrophages accumulated 7-ketocholesterol. These findings indicate a specific role for ABCG1 in promoting efflux of 7-ketocholesterol and related oxysterols from macrophages onto HDL and in protecting these cells from oxysterol-induced cytotoxicity.

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