Neimark Ezequiel, Chen Frank, Li Xiaoping, Shneider Benjamin L
Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hepatology. 2004 Jul;40(1):149-56. doi: 10.1002/hep.20295.
Ileal expression of the apical sodium-dependent bile acid transporter (ASBT) in the rat is unaffected by bile salts, yet in the mouse it is under negative-feedback regulation. The bile acid responsiveness of human ASBT is unknown. The human ASBT promoter linked to a luciferase reporter was studied in Caco-2 cells treated with chenodeoxycholic acid (CDCA) and transfected with expression plasmids for farnesoid X-receptor (FXR), short heterodimer partner (SHP), and retinoic acid receptor/retinoid X receptor (RAR/RXR). CDCA treatment of Caco-2 cells led to a 75% reduction in steady-state ASBT messenger RNA levels and a 78% reduction in human ASBT promoter activity. A dominant negative FXR abrogated the response to CDCA. Site-directed mutagenesis of an RAR/RXR cis element in the human ASBT promoter reduced its activity by 50% and eliminated the bile acid response. Retinoic acid activated the human ASBT promoter fourfold. SHP repressed the activity of the ASBT promoter and reduced activation by retinoic acid. Antisense mediated knock-down of SHP in Caco-2 cells partially offset the bile acid mediated repression of ASBT promoter activity. In conclusion, the human ASBT is positively regulated by retinoic acid. Bile acids induce a negative feedback regulation of human ASBT via an FXR-mediated, SHP-dependent effect upon RAR/RXR activation of ASBT.
大鼠回肠顶端钠依赖性胆汁酸转运体（ASBT）的表达不受胆盐影响，但在小鼠中它受到负反馈调节。人ASBT的胆汁酸反应性尚不清楚。将与人ASBT启动子连接的荧光素酶报告基因在经鹅去氧胆酸（CDCA）处理并转染了法尼酯X受体（FXR）、短异源二聚体伴侣（SHP）以及视黄酸受体/视黄酸X受体（RAR/RXR）表达质粒的Caco-2细胞中进行研究。用CDCA处理Caco-2细胞导致稳态ASBT信使RNA水平降低75%，人ASBT启动子活性降低78%。显性负性FXR消除了对CDCA的反应。对人ASBT启动子中一个RAR/RXR顺式元件进行定点诱变使其活性降低50%，并消除了胆汁酸反应。视黄酸使人类ASBT启动子活性增强四倍。SHP抑制ASBT启动子的活性，并降低视黄酸的激活作用。反义介导的Caco-2细胞中SHP基因敲低部分抵消了胆汁酸介导的ASBT启动子活性抑制。总之，人ASBT受视黄酸正调控。胆汁酸通过FXR介导的、SHP依赖的对ASBT的RAR/RXR激活的作用诱导人ASBT的负反馈调节。
