Division of Molecular Medicine, Department of Medicine, Columbia University, 630 W 168th Street, New York, NY 10032, USA.
Circ Res. 2011 Jan 21;108(2):194-200. doi: 10.1161/CIRCRESAHA.110.228619. Epub 2010 Dec 9.
Reduced plasma cholesterol and increased high-density lipoprotein (HDL) levels promote regression of atherosclerosis, in a process characterized by lipid unloading and emigration of macrophages from lesions. In contrast free cholesterol loading of macrophages leads to imbalanced Rac1/Rho activities and impaired chemotaxis.
To study the role of HDL and the ATP-binding cassette transporters ABCA1 and ABCG1 in modulating the chemotaxis of macrophages.
Abca1(-/-)Abcg1(-/-) mouse macrophages displayed profoundly impaired chemotaxis both in a Transwell chamber assay and in the peritoneal cavity of wild-type (WT) mice. HDL reversed impaired chemotaxis in free cholesterol-loaded WT macrophages but was without effect in Abca1(-/-)Abcg1(-/-) cells, whereas cyclodextrin was effective in both. Abca1(-/-)Abcg1(-/-) macrophages had markedly increased Rac1 activity and increased association of Rac1 with the plasma membrane (PM). Their defective chemotaxis was reversed by a Rac1 inhibitor. To gain a better understanding of the role of transporters in PM cholesterol movement, we measured transbilayer PM sterol distribution. In WT macrophages, the majority of cholesterol was located on the inner leaflet, whereas on upregulation of transporters by liver X receptor activation, PM sterol was shifted to the outer leaflet, where it could be removed by HDL. Abca1(-/-)Abcg1(-/-) macrophages showed increased PM sterol content and defective redistribution of sterol to the outer leaflet.
Deletion of ABCA1 and ABCG1 causes an increased cholesterol content on the inner leaflet of the PM, associated with increased Rac1 PM localization, activation, and impairment of migration. ABCA1 and ABCG1 facilitate macrophage chemotaxis by promoting PM transbilayer cholesterol movement and may contribute to the ability of HDL to promote regression of atherosclerosis.
降低血浆胆固醇和增加高密度脂蛋白（HDL）水平可促进动脉粥样硬化消退，其过程的特征为脂质卸载和病变中巨噬细胞的迁出。相比之下，巨噬细胞内游离胆固醇的加载会导致 Rac1/Rho 活性的失衡和趋化作用受损。
研究 HDL 以及 ATP 结合盒转运体 ABCA1 和 ABCG1 在调节巨噬细胞趋化作用中的作用。
Abca1(-/-)Abcg1(-/-) 鼠巨噬细胞在 Transwell 室测定和野生型（WT）鼠腹腔中显示出明显受损的趋化作用。HDL 逆转了游离胆固醇加载的 WT 巨噬细胞中受损的趋化作用，但对 Abca1(-/-)Abcg1(-/-)细胞无效，而环糊精则对两者均有效。Abca1(-/-)Abcg1(-/-) 巨噬细胞具有明显增加的 Rac1 活性和 Rac1 与质膜（PM）的结合增加。它们的缺陷趋化作用被 Rac1 抑制剂逆转。为了更好地理解转运蛋白在 PM 胆固醇运动中的作用，我们测量了跨双层 PM 甾醇分布。在 WT 巨噬细胞中，大多数胆固醇位于质膜的内叶，而当肝 X 受体激活上调转运蛋白时，PM 甾醇被转移到质膜的外叶，HDL 可以将其去除。Abca1(-/-)Abcg1(-/-) 巨噬细胞显示出增加的 PM 甾醇含量和甾醇向质膜外叶的缺陷再分布。
ABCA1 和 ABCG1 的缺失导致 PM 内叶的胆固醇含量增加，与 Rac1 PM 定位、激活和迁移受损相关。ABCA1 和 ABCG1 通过促进 PM 跨双层胆固醇运动促进巨噬细胞趋化作用，可能有助于 HDL 促进动脉粥样硬化消退。
