Zhou Xiaoye, He Wei, Huang Zhiping, Gotto Antonio M, Hajjar David P, Han Jihong
Center of Vascular Biology and Department of Pathology and Department of Medicine, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA.
J Biol Chem. 2008 Jan 25;283(4):2129-38. doi: 10.1074/jbc.M706636200. Epub 2007 Nov 20.
Low density lipoprotein receptor (LDLR) mutations cause familial hypercholesterolemia and early atherosclerosis. ABCA1 facilitates free cholesterol efflux from peripheral tissues. We investigated the effects of LDLR deletion (LDLR(-/-)) on ABCA1 expression. LDLR(-/-) macrophages had reduced basal levels of ABCA1, ABCG1, and cholesterol efflux. A high fat diet increased cholesterol in LDLR(-/-) macrophages but not wild type cells. A liver X receptor (LXR) agonist induced expression of ABCA1, ABCG1, and cholesterol efflux in both LDLR(-/-) and wild type macrophages, whereas expression of LXRalpha or LXRbeta was similar. Interestingly, oxidized LDL induced more ABCA1 in wild type macrophages than LDLR(-/-) cells. LDL induced ABCA1 expression in wild type cells but inhibited it in LDLR(-/-) macrophages in a concentration-dependent manner. However, lipoproteins regulated ABCG1 expression similarly in LDLR(-/-) and wild type macrophages. Cholesterol or oxysterols induced ABCA1 expression in wild type macrophages but had little or inhibitory effects on ABCA1 expression in LDLR(-/-) macrophages. Active sterol regulatory element-binding protein 1a (SREBP1a) inhibited ABCA1 promoter activity in an LXRE-dependent manner and decreased both macrophage ABCA1 expression and cholesterol efflux. Expression of ABCA1 in animal tissues was inversely correlated to active SREBP1. Oxysterols inactivated SREBP1 in wild type macrophages but not in LDLR(-/-) cells. Oxysterol synergized with nonsteroid LXR ligand induced ABCA1 expression in wild type macrophages but blocked induction in LDLR(-/-) cells. Taken together, our studies suggest that LDLR is critical in the regulation of cholesterol efflux and ABCA1 expression in macrophage. Lack of the LDLR impairs sterol-induced macrophage ABCA1 expression by a sterol regulatory element-binding protein 1-dependent mechanism that can result in reduced cholesterol efflux and lipid accumulation in macrophages under hypercholesterolemic conditions.
低密度脂蛋白受体（LDLR）突变会导致家族性高胆固醇血症和早期动脉粥样硬化。ABCA1促进外周组织中游离胆固醇的流出。我们研究了LDLR缺失（LDLR(-/-)）对ABCA1表达的影响。LDLR(-/-)巨噬细胞中ABCA1、ABCG1的基础水平以及胆固醇流出均降低。高脂饮食使LDLR(-/-)巨噬细胞中的胆固醇增加，但野生型细胞不受影响。肝脏X受体（LXR）激动剂可诱导LDLR(-/-)和野生型巨噬细胞中ABCA1、ABCG1的表达以及胆固醇流出，而LXRα或LXRβ的表达相似。有趣的是，氧化型LDL在野生型巨噬细胞中诱导产生的ABCA1比在LDLR(-/-)细胞中更多。LDL在野生型细胞中诱导ABCA1表达，但在LDLR(-/-)巨噬细胞中以浓度依赖的方式抑制其表达。然而，脂蛋白对LDLR(-/-)和野生型巨噬细胞中ABCG1表达的调节方式相似。胆固醇或氧化甾醇在野生型巨噬细胞中诱导ABCA1表达，但对LDLR(-/-)巨噬细胞中ABCA1的表达几乎没有影响或具有抑制作用。活性固醇调节元件结合蛋白1a（SREBP1a）以LXRE依赖的方式抑制ABCA1启动子活性，并降低巨噬细胞中ABCA1的表达和胆固醇流出。动物组织中ABCA1的表达与活性SREBP1呈负相关。氧化甾醇可使野生型巨噬细胞中的SREBP1失活，但在LDLR(-/-)细胞中则不然。氧化甾醇与非甾体LXR配体协同作用可诱导野生型巨噬细胞中ABCA1的表达，但在LDLR(-/-)细胞中则阻断这种诱导作用。综上所述，我们的研究表明LDLR在巨噬细胞中胆固醇流出和ABCA1表达的调节中起关键作用。LDLR的缺失通过一种固醇调节元件结合蛋白1依赖的机制损害了固醇诱导的巨噬细胞ABCA1表达，这可能导致在高胆固醇血症条件下巨噬细胞中胆固醇流出减少和脂质积累。
