Terasaka Naoki, Wang Nan, Yvan-Charvet Laurent, Tall Alan R
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15093-8. doi: 10.1073/pnas.0704602104. Epub 2007 Sep 10.
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.
饮食中摄入的或在低密度脂蛋白（LDL）上形成的氧化固醇对内皮细胞和巨噬细胞有毒性，并且被认为在促进动脉粥样硬化形成中起核心作用。ATP结合盒转运蛋白ABCG1最近被证明可促进巨噬细胞中的胆固醇外流至高密度脂蛋白（HDL）。我们发现HDL可保护巨噬细胞免受因加载游离胆固醇或氧化LDL而诱导的细胞凋亡。在Abcg1基因敲除（-/-）的巨噬细胞中，HDL的保护作用减弱，尤其是在加载氧化LDL之后。同样，HDL对由7-酮胆固醇诱导的细胞凋亡具有保护作用，7-酮胆固醇是氧化LDL和动脉粥样硬化病变中存在的主要氧化固醇，在野生型（Abcg1+/+）巨噬细胞中有效，但在Abcg1基因敲除（-/-）的巨噬细胞中无效。在转染的293细胞中，7-酮胆固醇和相关氧化固醇的外流完全依赖于ABCG1的表达以及培养基中HDL的存在。相比之下，ABCA1和载脂蛋白A-1不会刺激7-酮胆固醇外流至培养基中。HDL可刺激野生型（Abcg1+/+）巨噬细胞中的7-酮胆固醇外流，但不能刺激Abcg1基因敲除（-/-）的巨噬细胞。在喂食高胆固醇饮食的Abcg1基因敲除（-/-）小鼠中，血浆中7-酮胆固醇水平降低，而它们的巨噬细胞中积累了7-酮胆固醇。这些发现表明ABCG1在促进7-酮胆固醇和相关氧化固醇从巨噬细胞外流至HDL以及保护这些细胞免受氧化固醇诱导的细胞毒性方面具有特定作用。
