von Eckardstein A
Institute of Clinical Chemistry and Laboratory Medicine, Westfälische Wilhelms-Universität Münster, Germany.
Curr Opin Lipidol. 1996 Oct;7(5):308-19. doi: 10.1097/00041433-199610000-00009.
Foam cell formation by lipid accumulation in macrophages is a prominent finding in atherosclerotic plaques. Since macrophages cannot limit the uptake of lipids, cholesterol efflux is probably essential to inhibit progression and cause regression of atherosclerosis. Cholesterol efflux is generally attributed to HDL in the extracellular space. Slow bidirectional fluxes of cholesterol occur between plasma membrane and lipid-rich HDL subclasses. Esterification of cholesterol in HDL by lecithin: cholesterol acyltransferase causes net cholesterol efflux. In contrast, some lipid-free apolipoproteins (especially apolipoprotein A-I) and lipid-poor HDL subclasses such as prebeta 1-apolipoprotein A-I containing lipoprotein mediate rapid and unidirectional cholesterol efflux from specific cholesterol domains in the plasma membrane. Extracellular presence of HDL or apolipoprotein A-I moreover facilitates the translocation of cholesterol from intracellular pools to the plasma membrane, probably via signal transduction. The activated transfer machinery appears to involve the Golgi apparatus and diverts cholesterol from the shuttle between acylcoenzyme A: cholesterol acyltransferase and neutral cholesteryl ester hydrolase (cholesteryl ester cycle). Endogenously synthesized apolipoprotein E facilitates HDL-mediated cholesterol efflux from macrophages. Moreover, at least in human monocyte-derived macrophages, apolipoprotein E appears to be involved in the export of cholesterol independently from extracellular acceptors. Cholesterol efflux can be inhibited by some oxysterols that are found in macrophages of atherosclerotic plaques and macrophages that are loaded in vitro with oxidized LDL.
巨噬细胞中脂质蓄积形成泡沫细胞是动脉粥样硬化斑块的一个显著特征。由于巨噬细胞无法限制脂质摄取，胆固醇外流可能对抑制动脉粥样硬化进展及促使其消退至关重要。胆固醇外流一般归因于细胞外空间的高密度脂蛋白（HDL）。胆固醇在质膜和富含脂质的HDL亚类之间缓慢双向流动。卵磷脂胆固醇酰基转移酶使HDL中的胆固醇酯化导致胆固醇净外流。相比之下，一些无脂质载脂蛋白（尤其是载脂蛋白A-I）和脂质含量低的HDL亚类，如含前β1-载脂蛋白A-I的脂蛋白，介导胆固醇从质膜特定胆固醇区域快速单向外流。此外，HDL或载脂蛋白A-I的细胞外存在可能通过信号转导促进胆固醇从细胞内池转运至质膜。激活的转运机制似乎涉及高尔基体，并使胆固醇从酰基辅酶A：胆固醇酰基转移酶与中性胆固醇酯水解酶之间的穿梭（胆固醇酯循环）中转移出来。内源性合成的载脂蛋白E促进HDL介导的巨噬细胞胆固醇外流。此外，至少在人单核细胞衍生的巨噬细胞中，载脂蛋白E似乎独立于细胞外受体参与胆固醇的输出。胆固醇外流可被一些在动脉粥样硬化斑块巨噬细胞以及体外加载氧化低密度脂蛋白的巨噬细胞中发现的氧化固醇抑制。
