Murthy Shubha, Born Ella, Mathur Satya N, Field F Jeffrey
Department of Veterans Affairs and Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
J Lipid Res. 2002 Jul;43(7):1054-64. doi: 10.1194/jlr.m100358-jlr200.
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 ABCG1 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 ABCG1 and the basolateral efflux of cholesterol, suggesting that ABCA1 plays an important role in intestinal HDL production and cholesterol absorption.
在人肠上皮细胞系CaCo-2中研究了肝脏X受体/视黄酸X受体（LXR/RXR）配体对ATP结合盒转运蛋白（ABC）A1和ABCG1基因表达的调控。视黄酸X受体（RXR）配体9-顺式视黄酸和天然LXR配体22-羟基胆固醇单独使用时均未改变ABCA1 mRNA水平。两者共同添加时，ABCA1和ABCG1 mRNA水平分别增加了3倍和7倍。合成的非甾体LXR激动剂T0901317分别使ABCA1和ABCG1基因表达增加了11倍和6倍。LXR/RXR激活增加了ABCA1的量。T0901317或9-顺式视黄酸与22-羟基胆固醇增加了基底外侧而非顶端膜的胆固醇流出。LXR/RXR配体使胆固醇向载脂蛋白（apo）A-I或高密度脂蛋白（HDL）的流出增加，但向牛磺胆酸盐/磷脂酰胆碱微团的流出未增加。放线菌素D可阻止配体诱导的ABCA1和ABCG1 mRNA水平升高以及胆固醇流出增加。ABCA1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激活减少了源自质膜的胆固醇酯的酯化和分泌。因此，在CaCo-2细胞中，LXR/RXR激活增加了ABCA1和ABCG1的基因表达以及基底外侧胆固醇流出，提示ABCA1在肠道HDL产生和胆固醇吸收中起重要作用。
