Epoxycholesterol impairs cholesteryl ester hydrolysis in macrophage foam cells, resulting in decreased cholesterol efflux
Epoxycholesterol impairs cholesteryl ester hydrolysis in macrophage foam cells, resulting in decreased cholesterol efflux
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DOI：
10.1161/atvbaha.107.157115
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发表时间：
2008-06-01
影响因子：
8.7
通讯作者：
Marcel, Yves L.
中科院分区：
文献类型：
--
作者：
Ouimet, Mireille;Wang, Ming-Dong;Marcel, Yves L.
目的：抑制或逆转巨噬细胞中胆固醇积累的策略已被证明具有动脉粥样硬化保护作用。值得注意的是，LXR激动剂的使用上调了逆向胆固醇转运途径中的关键参与者，包括ABCA1和ABCG1转运蛋白。然而，天然LXR激活剂，氧化甾醇，对脂质巨噬细胞的影响仍然是难以捉摸的。方法和结果-我们评估了2种氧甾醇，22(R)-羟基胆固醇（22- oh）和24(S)， 25-环氧胆固醇（环氧胆固醇），促进胆固醇从LDL-和修饰LDL标记和负载的巨噬细胞外流到apoA-I的能力，从而挽救了这些细胞中与细胞胆固醇积累相关的表型。在ldl来源胆固醇标记的巨噬细胞中，环氧胆固醇处理增强了abca1介导的胆固醇外排。相反，在负荷acldl的巨噬细胞中，尽管ABCA1的表达在环氧胆固醇处理下急剧增加，但环氧胆固醇处理减少了胆固醇向apoA-I的外排。我们的研究表明，外排减少是由于胆固醇酯水解酶活性降低导致的脂滴胆固醇动员受损。结论：环氧胆固醇损害巨噬细胞泡沫细胞的胆固醇酯水解活性，从而降低胆固醇向胆固醇受体外排的可用性。
Objective-Strategies to inhibit or reverse cholesterol accumulation in macrophages have been shown to be atheroprotective. Notably, the administration of LXR agonists upregulates key players in the reverse cholesterol transport pathway, including the ABCA1 and ABCG1 transporters. However, the effects of natural LXR activators, oxysterols, on lipid-laden macrophages remains elusive.Methods and Results-We assessed the ability of 2 oxysterols, 22(R)-hydroxycholesterol (22-OH) and 24(S), 25-epoxycholesterol (epoxycholesterol), to promote cholesterol efflux to apoA-I from LDL- and modified LDL-labeled and loaded macrophages and thus rescue the phenotype associated with the accumulation of cellular cholesterol in these cells. In macrophages labeled with LDL-derived cholesterol, epoxycholesterol treatment enhances ABCA1-mediated cholesterol efflux. In contrast, in AcLDL-loaded macrophages, epoxycholesterol treatment decreases cholesterol efflux to apoA-I, despite a dramatic increase in the expression of ABCA1 in response to epoxycholesterol treatment. We show that the decreased efflux is attributable to impaired cholesterol mobilization from lipid droplets, resulting from decreased cholesteryl ester hydrolase activity.Conclusion-Epoxycholesterol impairs cholesteryl ester hydrolysis activity in macrophage foam cells, thus reducing the availability of cholesterol for efflux to cholesterol acceptors.