ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells

被引:45
作者
Tam, Shui-Pang
Mok, Leo
Chimini, Giovanna
Vasa, Monika
Deeley, Roger G.
机构
[1] Queens Univ, Canc Res Inst, Div Canc Biol & Genet, Kingston, ON K7L 3N6, Canada
[2] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada
[3] Univ Mediterranee, CNRS, INSERM, Ctr Immunol Luminy, Marseille, France
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2006年 / 291卷 / 03期
关键词
active transport; cholesterol homeostasis;
D O I
10.1152/ajpcell.00055.2006
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
ATP Binding Cassette (ABC) transporter, ABCA1, plays a pivotal role in reverse cholesterol transport by mediating the cellular efflux of phospholipid and cholesterol. Studies using intact cells strongly suggest that ABCA1 acts as a phospholipid floppase, but there has been no direct demonstration that the protein is a primary active sterol transporter. Using membrane vesicles from insect Sf21 cells, we found that ABCA1 mediated ATP-dependent uptake of [H-3]25-hydroxycholesterol with an apparent K-m of 0.7 mu M. Consistent with this high apparent affinity, expression of ABCA1 in human embryonic kidney cells both increased rapid efflux of 25-hydroxcholesterol and prevented oxysterol-mediated repression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNAs. Comparison of wild-type and ABCA1(-/-) murine fibroblasts indicates that 25-hydroxycholesterol is effluxed similar to 5-fold more rapidly by wild-type cells. In addition, the rate of efflux from the wild-type but not the ABCA1(-/-) fibroblasts is increased a further twofold by inducers of ABCA1 expression. Thus under the experimental conditions employed, endogenous ABCA1 is a major contributor to 25-hydroxycholesterol efflux from wild-type fibroblasts. Evidence from in vitro studies indicates that oxysterols are potent inducers of genes involved in cellular cholesterol efflux and metabolism, including the ABCA1 gene, and repressors of genes involved in cholesterol synthesis or uptake. Our observations raise the possibility that efflux of oxysterols by ABCA1 could contribute to a homeostatic mechanism, which both attenuates oxysterol-induced expression of its cognate gene and alleviates repression of genes encoding proteins, such as HMG-CoA reductase and LDL receptor.
引用
收藏
页码:C490 / C502
页数:13
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