NR1H2,3 binds the ABCG8 gene

Liver X receptor alpha (LXRα or NR1H3) is regarded as the major regulator of the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 mRNA expression. The synthetic agonist T0901317 of NR1H2, 3 markedly upregulated ABCG5 and ABCG8 expression in the small intestine and liver of wild type, but not NR1H3-knockout mice (Repa JJ et al. 2002; van der Veen et al. 2007). The human ABCG5 and ABCG8 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species. Using a reporter construct, the intergenic region was found to act as a bidirectional promoter and to harbor binding sites for hepatocyte nuclear factor 4α (HNF4α), liver receptor homolog 1 (LRH1) and GATA transcription factors (Remaley AT et al. 2002; Sumi K et al. 2007; Freeman LA et al. 2004). Through elaborate deletion studies, two regions containing putative LXR responsive elements (LXRE) were identified in ABCG5 and ABCG8 genes (Back SS et al. 2013). Electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP) and cell reporter assays demonstrated the binding of NR1H3 (and RXR) to two intronic regions of the human ABCG8 gene to confer LXR-mediated regulation of ABCG5 and ABCG8 genes in human liver carcinoma HepG2 cells (Back SS et al. 2013).<p>In mammalian cells, ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for developing premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001).

肝X受体α（LXRα或NR1H3）被视为调节腺苷三磷酸（ATP）结合 cassette（ABC）转运蛋白ABCG5和ABCG8 mRNA表达的主要调控因子。NR1H2，3的合成激动剂T0901317在野生型小鼠的小肠和肝脏中显著上调了ABCG5和ABCG8的表达，但在NR1H3敲除小鼠中却未观察到此现象（Repa JJ等，2002；van der Veen等，2007）。人类ABCG5和ABCG8基因，每个基因均含有13个外显子，位于第2号染色体短臂2p21上的相邻位置，呈头对头配置（Remaley AT等，2002）。它们的开码子之间隔有374个碱基对的基因间区域，该区域在多个物种中高度保守。利用报告基因构建，发现该基因间区域充当双向启动子，并含有肝细胞核因子4α（HNF4α）、肝受体同源物1（LRH1）和GATA转录因子的结合位点（Remaley AT等，2002；Sumi K等，2007；Freeman LA等，2004）。通过精细的缺失研究，在ABCG5和ABCG8基因中确定了两个含有潜在LXR反应元件（LXRE）的区域（Back SS等，2013）。电泳迁移率变动（EMSA）、染色质免疫沉淀（ChIP）和细胞报告实验表明，NR1H3（及RXR）与人类ABCG8基因的两个内含子区域结合，从而在人类肝癌细胞HepG2细胞中赋予ABCG5和ABCG8基因以LXR介导的调节作用（Back SS等，2013）。在哺乳动物细胞中，ABCG5和ABCG8形成异源二聚体，限制肠道对膳食类固醇的吸收，并通过肝胆分泌促进胆固醇从体内排出（Berge KE等，2000；Graf GA等，2002，2003；由Yu XH等综述，2014）。与这些功能一致，ABCG5和ABCG8几乎仅表达于肠细胞的刷状缘膜和肝细胞的管状膜上（Yu XH等，2014）。ABCG5和ABCG8的突变是致淀粉样动脉硬化症的原因，这是一种遗传性疾病，患者血液中胆固醇和植物固醇积累，且发生早发性心血管疾病的风险增加（Berge KE等，2000；Lee MH等，2001）。