Choy Henry A, Wang Xu-Ping, Schotz Michael C
Lipid Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Biochim Biophys Acta. 2003 Nov 15;1634(3):76-85. doi: 10.1016/j.bbalip.2003.09.001.
Macrophage-specific overexpression of cholesteryl ester hydrolysis in hormone-sensitive lipase transgenic (HSL Tg) female mice paradoxically increases cholesterol esterification and cholesteryl ester accumulation in macrophages, and thus susceptibility to diet-induced atherosclerosis compared to nontransgenic C57BL/6 mice. The current studies suggest that whereas increased cholesterol uptake could contribute to transgenic foam cell formation, there are no differences in cholesterol synthesis and the expression of cholesterol efflux mediators (ABCA1, ABCG1, apoE, PPARgamma, and LXRalpha) compared to wild-type macrophages. HSL Tg macrophages exhibit twofold greater efflux of cholesterol to apoA-I in vitro, suggesting the potential rate-limiting role of cholesteryl ester hydrolysis in efflux. However, macrophage cholesteryl ester levels appear to depend on the relative efficacy of alternate pathways for free cholesterol in either efflux or re-esterification. Thus, increased atherosclerosis in HSL Tg mice appears to be due to the coupling of the efficient re-esterification of excess free cholesterol to its limited removal mediated by the cholesterol acceptors in these mice. The overexpression of cholesterol acceptors in HSL-apoA-IV double-transgenic mice increases plasma HDL levels and decreases diet-induced atherosclerosis compared to HSL Tg mice, with aortic lesions reduced to sizes in nontransgenic littermates. The results in vivo are consistent with the effective efflux from HSL Tg macrophages supplemented with HDL and apoA-I in vitro, and highlight the importance of cholesterol acceptors in inhibiting atherosclerosis caused by imbalances in the cholesteryl ester cycle.
在激素敏感脂肪酶转基因（HSL Tg）雌性小鼠中，巨噬细胞特异性过表达胆固醇酯水解酶，与非转基因C57BL/6小鼠相比，反而会增加巨噬细胞中胆固醇酯化和胆固醇酯积累，进而增加饮食诱导的动脉粥样硬化易感性。目前的研究表明，虽然胆固醇摄取增加可能有助于转基因泡沫细胞形成，但与野生型巨噬细胞相比，胆固醇合成以及胆固醇流出介质（ABCA1、ABCG1、载脂蛋白E、PPARγ和LXRα）的表达并无差异。HSL Tg巨噬细胞在体外向载脂蛋白A-I的胆固醇流出增加两倍，提示胆固醇酯水解在流出中可能起限速作用。然而，巨噬细胞胆固醇酯水平似乎取决于游离胆固醇在流出或重新酯化的替代途径的相对效率。因此，HSL Tg小鼠动脉粥样硬化增加似乎是由于过量游离胆固醇的有效重新酯化与其在这些小鼠中由胆固醇受体介导的有限清除之间的耦合。与HSL Tg小鼠相比，HSL-载脂蛋白A-IV双转基因小鼠中胆固醇受体的过表达增加了血浆高密度脂蛋白水平，并减少了饮食诱导的动脉粥样硬化，主动脉病变缩小至非转基因同窝小鼠的大小。体内结果与体外补充高密度脂蛋白和载脂蛋白A-I的HSL Tg巨噬细胞的有效流出一致，并突出了胆固醇受体在抑制胆固醇酯循环失衡引起的动脉粥样硬化中的重要性。
