Wang Nan, Lan Debin, Chen Wengen, Matsuura Fumihiko, Tall Alan R
Department of Medicine, Division of Molecular Medicine, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9774-9. doi: 10.1073/pnas.0403506101. Epub 2004 Jun 21.
The mechanisms responsible for the inverse relationship between plasma high-density lipoprotein (HDL) levels and atherosclerotic cardiovascular disease are poorly understood. The ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to lipid-poor apolipoproteins but not to HDL particles that constitute the bulk of plasma HDL. We show that two ABC transporters of unknown function, ABCG1 and ABCG4, mediate isotopic and net mass efflux of cellular cholesterol to HDL. In transfected 293 cells, ABCG1 and ABCG4 stimulate cholesterol efflux to both smaller (HDL-3) and larger (HDL-2) subclasses but not to lipid-poor apoA-I. Treatment of macrophages with an liver X receptor activator results in up-regulation of ABCG1 and increases cholesterol efflux to HDL. RNA interference reduced the expression of ABCG1 in liver X receptor-activated macrophages and caused a parallel decrease in cholesterol efflux to HDL. These studies indicate that ABCG1 and ABCG4 promote cholesterol efflux from cells to HDL. ABCG1 is highly expressed in macrophages and probably mediates cholesterol efflux from macrophage foam cells to the major HDL fractions, providing a mechanism to explain the relationship between HDL levels and atherosclerosis risk.
血浆高密度脂蛋白(HDL)水平与动脉粥样硬化性心血管疾病之间呈负相关的机制目前尚不清楚。ATP结合盒转运蛋白A1(ABCA1)介导细胞胆固醇向脂质含量低的载脂蛋白外流,但不介导向构成血浆HDL主体的HDL颗粒外流。我们发现两种功能未知的ABC转运蛋白ABCG1和ABCG4介导细胞胆固醇向HDL的同位素外流和净质量外流。在转染的293细胞中,ABCG1和ABCG4促进胆固醇向较小(HDL-3)和较大(HDL-2)亚类外流,但不向脂质含量低的载脂蛋白A-I外流。用肝脏X受体激活剂处理巨噬细胞会导致ABCG1上调,并增加胆固醇向HDL的外流。RNA干扰降低了肝脏X受体激活的巨噬细胞中ABCG1的表达,并导致胆固醇向HDL外流平行减少。这些研究表明,ABCG1和ABCG4促进细胞内胆固醇向HDL外流。ABCG1在巨噬细胞中高度表达,可能介导巨噬细胞泡沫细胞中的胆固醇向主要HDL组分外流,从而提供了一种机制来解释HDL水平与动脉粥样硬化风险之间的关系。