Delerive Philippe, Galardi Cristin M, Bisi John E, Nicodeme Edwige, Goodwin Bryan
GlaxoSmithKline, Cardiovascular & Urogenital Center of Excellence for Drug Discovery, 91951 Les Ulis, France.
Mol Endocrinol. 2004 Oct;18(10):2378-87. doi: 10.1210/me.2004-0132. Epub 2004 Jun 24.
The orphan nuclear receptor liver receptor homolog-1 (LRH-1) has been reported to play a role in bile acid biosynthesis and reverse cholesterol transport. In this study, we examined the role of LRH-1 in the regulation of the apolipoprotein AI (APOAI) gene. Using RNA interference and adenovirus-mediated overexpression, we show that LRH-1 directly regulates APOAI gene transcription. Transient transfection experiments and EMSAs revealed that LRH-1 directly regulates APOAI transcription by binding to an LRH-1 response element located in the proximal APOAI promoter region. Chromatin immunoprecipitation experiments revealed that LRH-1 binds to the human APO AI promoter in vivo. Finally, we show that the transcriptional repressor SHP (small heterodimer partner) suppressed APOAI gene expression by inhibiting LRH-1 transcriptional activity. Taken together, our results demonstrate that LRH-1 is a novel regulator of APOAI transcription and underscore the role of this receptor in cholesterol homeostasis.
据报道，孤儿核受体肝受体同源物1（LRH-1）在胆汁酸生物合成和逆向胆固醇转运中发挥作用。在本研究中，我们研究了LRH-1在载脂蛋白AI（APOAI）基因调控中的作用。使用RNA干扰和腺病毒介导的过表达，我们表明LRH-1直接调节APOAI基因转录。瞬时转染实验和电泳迁移率变动分析表明，LRH-1通过与位于APOAI启动子近端区域的LRH-1反应元件结合来直接调节APOAI转录。染色质免疫沉淀实验表明，LRH-1在体内与人APO AI启动子结合。最后，我们表明转录抑制因子SHP（小异源二聚体伴侣）通过抑制LRH-1转录活性来抑制APOAI基因表达。综上所述，我们的结果表明LRH-1是APOAI转录的新型调节因子，并强调了该受体在胆固醇稳态中的作用。
