The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter
The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter
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DOI：
10.1194/jlr.c400002-jlr200
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发表时间：
2004-07-01
影响因子：
6.5
通讯作者：
Brewer, HB
中科院分区：
文献类型：
--
作者：
Freeman, LA;Kennedy, A;Brewer, HB
ATP结合盒（ABC）半转运蛋白ABCG 5和ABCG 8促进中性固醇的胆汁和肠道清除。在这里，我们确定了孤儿核受体肝受体同源物-1（LRH-1）的结合位点，该位点位于ABCG 5和ABCG 8启动子活性所必需的ABCG 5/ABCG 8基因间区域的nt 134 - 142。在HepG2和Caco 2细胞中，突变LRH-1结合位点使人ABCG 5/ABCG 8基因间区的启动子活性降低7倍以上。用HepG2细胞核提取物进行的电泳迁移率变动分析表明，LRH-1与人ABCG 5/ABCG 8基因间区域中的LRH-1结合基序特异性结合。LRH-1过表达增加启动子活性高达1.6倍和3倍，分别在Caco 2和293细胞。最后，脱氧胆酸抑制ABCG 5和ABCG 8启动子，与胆汁酸通过法尼醇X受体-小异源二聚体伴侣-LRH-1途径调节一致。这些结果表明，LRH-1是ABCG 5和ABCG 8的正转录因子，并结合对LRH-1激活其他启动子的研究，将LRH-1鉴定为参与肝脏和肠道固醇和胆汁酸分泌的基因的"主调节因子"。弗里曼湖，澳-地一、a. Kennedy，J. Wit，S. Bark，A. t.雷马利，S。Santamarina-Fojo和H. B。小布鲁尔孤儿核受体LRH-1激活ABCG5/ABCG8基因间启动子。
The ATP binding cassette (ABC) half-transporters ABCG5 and ABCG8 facilitate biliary and intestinal removal of neutral sterols. Here, we identify a binding site for the orphan nuclear receptor liver receptor homolog-1 (LRH-1) at nt 134-142 of the ABCG5/ABCG8 intergenic region necessary for the activity of both the ABCG5 and ABCG8 promoters. Mutating this LRH-1 binding site reduced promoter activity of the human ABCG5/ABCG8 intergenic region more than 7-fold in HepG2 and Caco2 cells. Electrophoretic mobility shift assays with HepG2 nuclear extracts demonstrated specific binding of LRH-1 to the LRH-1 binding motif in the human ABCG5/ABCG8 intergenic region. LRH-1 overexpression increased promoter activity up to 1.6-fold and 3-fold in Caco2 and 293 cells, respectively. Finally, deoxycholic acid repressed the ABCG5 and ABCG8 promoters, consistent with bile acid regulation via the farnesoid X receptor-small heterodimeric partner-LRH-1 pathway. These results demonstrate that LRH-1 is a positive transcription factor for ABCG5 and ABCG8 and, in conjunction with studies on LRH-1 activation of other promoters, identify LRH-1 as a "master regulator" for genes involved in sterol and bile acid secretion from liver and intestine.-Freeman, L. A., A. Kennedy, J. Wit, S. Bark, A. T. Remaley, S. Santamarina-Fojo, and H. B. Brewer,Jr. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter.