Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver
Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver
复制标题
DOI：
10.1016/j.bbamem.2009.08.014
复制
发表时间：
2009-11-01
影响因子：
3.4
通讯作者：
Iseki, Ken
中科院分区：
文献类型：
--
作者：
Chisaki, Ikumi;Kobayashi, Masaki;Iseki, Ken
肝X受体（LXRs）属于核激素受体超家族。多药耐药相关蛋白2（MRP 2）、多药耐药蛋白1（MDR 1）和乳腺癌耐药蛋白（BCRP）在肝细胞内源性和外源性化合物的外排中起重要作用。由于LXR激活对三种转运蛋白的影响尚不清楚，我们研究了LXR激动剂TO 901317和25-羟基胆固醇对HepG 2细胞和大鼠肝脏中MRP 2、MDR 1、BCRP表达的影响。在一项体外研究中，TO 901317增加了ABCA 1（一种LXR靶基因）以及MRP 2 mRNA和蛋白水平。另一方面，TO 901317对MDR 1和BCRP mRNA水平几乎没有影响。在体内研究中，TO 901317可增加Abca 1和Mrp 2 mRNA和蛋白水平。而TO 901317对大鼠肝脏Mdr 1a和Bcrp mRNA水平无影响。此外，TO 901317诱导的MRP 2 mRNA表达被LXR α敲低阻断。在这项研究中，我们证明了LXR激活诱导肝细胞中MRP 2的表达，但不诱导MDR 1和BCRP的表达。结果表明，LXR激动剂激活MRP 2基因的转录，以促进内源性和外源性化合物从肝细胞分泌到胆汁中。(C)2009爱思唯尔有限公司版权所有。
Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily. Multidrug resistance-associated protein 2 (MRP2), multidrug resistance 1 (MDR1) and breast cancer resistance protein (BCRP) play an important role in the efflux of a broad range of endogenous and xenobiotic compounds from hepatocytes. Since the effects of LXR activation on there transporters have been obscure, we investigated the effects of LXR agonists, TO901317 and 25-hydroxycholesterol, on MRP2, MDR1, BCRP expression in HepG2 cells and the rat liver. in an in vitro study, TO901317 increased ABCA1, an LXR target gene, and MRP2 mRNA and protein levels. On the other hand, TO901317 had little effect on MDR1 and BCRP mRNA levels. In an in vivo study, Abca1 and Mrp2 mRNA and protein levels were increased by TO901317. but TO901317 had no effect on Mdr1a and Bcrp mRNA levels in the rat liver. Moreover, TO901317-induced MRP2 mRNA expression was blocked by LXR alpha knockdown. In this study, we demonstrated that LXR activation induced expression of MRP2 but not that of MDR1 and BCRP in hepatocytes. The results suggest that agonists for LXR activate transcription of the MRP2 gene in order to promote excretion of endogenous and xenobiotic compounds from hepatocytes into bile. (C) 2009 Elsevier B.V. All rights reserved.