Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter
Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter
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DOI：
10.1074/jbc.m207903200
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发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
Shneider, BL
中科院分区：
文献类型：
--
作者：
Chen, F;Ma, L;Shneider, BL
小肠回收胆汁盐在很大程度上由顶端钠依赖性胆汁酸转运蛋白（ASBT）介导。ASBT的胆汁酸反应性是有争议的。小鼠胆汁酸喂养导致ASBT蛋白和mRNA表达降低。在Caco-2细胞中，鹅去氧胆酸抑制了小鼠而非大鼠ASBT启动子活性，但未抑制IEC-6细胞。一个潜在的肝受体同源物-1（LRH-1）的顺式作用元件被确定在小鼠的胆汁酸反应区，但不是大鼠的启动子。小鼠而不是大鼠启动子被LRH-1激活，这与核蛋白结合小鼠而不是大鼠LRH-1元件相关。短的异源二聚体伴侣降低了小鼠启动子的活性，并可部分抵消LRH-1对其的激活。小鼠和大鼠ASBT启动子之间潜在的LRH-1顺式元件的相互转换与LRH-1和胆汁酸反应性的相互转换有关。在Caco-2细胞和小鼠回肠中发现LRH-1蛋白，而在IEC-6细胞和大鼠回肠中没有发现。胆汁酸反应是由法尼醇X受体介导的，如显性负性法尼醇X受体的过表达消除了胆汁酸介导的ASBT下调的事实所示。此外，ASBT在法尼醇X受体缺失小鼠中的表达对胆汁酸喂养无反应。总之，胆汁酸对ASBT的细胞系和物种特异性负反馈调节是由法尼醇X受体介导的，通过小的异源二聚体伴侣依赖性抑制ASBT启动子的LRH-1活化。
Intestinal reclamation of bile salts is mediated in large part by the apical sodium-dependent bile acid transporter (ASBT). The bile acid responsiveness of ASBT is controversial. Bile acid feeding in mice results in decreased expression of ASBT protein and mRNA. Mouse but not rat ASBT promoter activity was repressed in Caco-2, but not IEC-6, cells by chenodeoxycholic acid. A potential liver receptor homologue-1 (LRH-1) cis-acting element was identified in the bile acid-responsive region of the mouse but not rat promoter. The mouse, but not rat, promoter was activated by LRH-1, and this correlated with nuclear protein binding to the mouse but not rat LRH-1 element. The short heterodimer partner diminished the activity of the mouse promoter and could partially offset its activation by LRH-1. Interconversion of the potential LRH-1 cis-elements between the mouse and rat ASBT promoters was associated with an interconversion of LRH-1 and bile acid responsiveness. LRH-1 protein was found in Caco-2 cells and mouse ileum, but not IEC-6 cells or rat ileum. Bile acid response was mediated by the farnesoid X receptor, as shown by the fact that overexpression of a dominant-negative farnesoid X-receptor eliminated the bile acid mediated down-regulation of ASBT. In addition, ASBT expression in farnesoid X receptor null mice was unresponsive to bile acid feeding. In summary cell line- and species-specific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner-dependent repression of LRH-1 activation of the ASBT promoter.