LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells
LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells
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DOI：
10.1194/jlr.m100358-jlr200
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发表时间：
2002-07-01
影响因子：
6.5
通讯作者：
Field, FJ
中科院分区：
文献类型：
--
作者：
Murthy, S;Born, E;Field, FJ
在人肠细胞系CaCo-2中研究了肝X受体/维甲酸X受体（LXR/RXR）配体对ATP结合盒转运体（ABC）A1和ABCG 1基因表达的调节。无论是RXR配体，9-顺式视黄酸，也不是天然LXR配体22-羟基胆固醇单独改变ABCA 1 mRNA水平。当加在一起时，ABCA 1和ABCG 1 mRNA水平分别增加了3倍和7倍。T0901317是一种合成的非固醇LXR激动剂，可使ABCA 1和ABCG 1基因表达分别增加11倍和6倍。ABCA 1质量通过LXR/RXR活化而增加。T0901317或9-顺式视黄酸和22-羟基胆固醇增加胆固醇从基底外侧膜流出，但不增加顶膜流出。胆固醇流出增加的LXR/ RXR配体载脂蛋白（apo）A-I或HDL，但不牛磺胆酸盐/磷脂酰胆碱胶束。放线菌素D阻止ABCA 1和ABCGI mRNA水平的增加以及配体诱导的胆固醇流出的增加。ABCA 1活性抑制剂格列本脲可减弱T0901317诱导的基底外侧胆固醇流出增加。LXR/RXR激活降低了来自质膜的胆固醇酯的酯化和分泌。因此，在CaCo-2细胞中，LXR/RXR激活增加ABCA 1和ABCGI的基因表达以及胆固醇的基底外侧流出，表明ABCA 1在肠HDL产生和胆固醇吸收中起重要作用。
Regulation of gene expression of ATP-binding cassette transporter (ABC)A1 and ABCG1 by liver X receptor/retinoid X receptor (LXR/RXR) ligands was investigated in the human intestinal cell line CaCo-2. Neither the RXR ligand, 9-cis retinoic acid, nor the natural LXR ligand 22-hydroxycholesterol alone altered ABCA1 mRNA levels. When added together, ABCA1 and ABCG1 mRNA levels were increased 3- and 7-fold, respectively. T0901317, a synthetic non-sterol LXR agonist, increased ABCA1 and ABCG1 gene expression 11- and 6-fold, respectively. ABCA1 mass was increased by LXR/RXR activation. T0901317 or 9-cis retinoic acid and 22-hydroxycholesterol increased cholesterol efflux from basolateral but not apical membranes. Cholesterol efflux was increased by the LXR/ RXR ligands to apolipoprotein (apo)A-I or HDL but not to taurocholate/phosphatidylcholine micelles. Actinomycin D prevented the increase in ABCA1 and ABCGI mRNA levels and the increase in cholesterol efflux induced by the ligands. Glyburide, an inhibitor of ABCA1 activity, attenuated the increase in basolateral cholesterol efflux induced by T0901317. LXR/RXR activation decreased the esterification and secretion of cholesterol esters derived from plasma membranes. Thus, in CaCo-2 cells, LXR/RXR activation increases gene expression of ABCA1 and ABCGI and the basolateral efflux of cholesterol, suggesting that ABCA1 plays an important role in intestinal HDL production and cholesterol absorption.