Pan Debra H, Chen Frank, Neimark Ezequiel, Li Xiaoping, Shneider Benjamin L
Department of Pediatrics, Division of Pediatric Hepatology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1656, New York, NY 10029, USA.
Biochim Biophys Acta. 2005 Dec 30;1732(1-3):31-7. doi: 10.1016/j.bbaexp.2006.01.003. Epub 2006 Jan 26.
The apical sodium dependent bile acid transporter (ASBT) mediates ileal bile acid reabsorption. The transcription factors, liver receptor homologue-1 (LRH-1:mouse) and fetoprotein transcription factor (FTF:human), are presumably orthologues. Bile-acid induced negative feedback regulation of mouse (m) and human (h) ASBT occurs via LRH-1 and RAR/RXR, respectively. hASBT has a potential FTF cis-element, although its functional role is unknown. hASBT and mASBT promoter constructs and an FTF cis-element mutated hASBT (hASBT/FTFmu) were assessed in human Caco-2 cells treated with chenodeoxycholic acid (CDCA) and/or co-transfected with hFTF, mLRH-1, or specific small interfering FTF or LRH-1 RNA (siFTF or siLRH). Basal promoter activity was reduced in hASBT/FTFmu, although bile acid response persisted. hFTF activated hASBT but not mASBT, while mLRH-1 activated mASBT but not hASBT. siFTF reduced hASBT but not mASBT activity; siLRH reduced mASBT but not hASBT activity. siLRH but not siFTF abrogated bile acid responsiveness. Electrophoretic mobility shift assays demonstrated distinct and specific binding of the mLRH-1 or hFTF cis-elements. In conclusion, FTF and LRH-1 are two related but different transcription factors in human Caco-2 cells, suggesting that they may be homologues and not orthologues. FTF is not involved directly in bile acid mediated negative feedback regulation of the ASBT.
顶端钠依赖性胆汁酸转运蛋白（ASBT）介导回肠胆汁酸重吸收。转录因子肝受体同源物-1（LRH-1：小鼠）和甲胎蛋白转录因子（FTF：人类）可能是直系同源物。小鼠（m）和人类（h）ASBT的胆汁酸诱导负反馈调节分别通过LRH-1和RAR/RXR发生。hASBT有一个潜在的FTF顺式作用元件，但其功能作用尚不清楚。在经鹅去氧胆酸（CDCA）处理和/或与hFTF、mLRH-1或特异性小干扰FTF或LRH-1 RNA（siFTF或siLRH）共转染的人Caco-2细胞中评估hASBT和mASBT启动子构建体以及FTF顺式作用元件突变的hASBT（hASBT/FTFmu）。hASBT/FTFmu的基础启动子活性降低，尽管胆汁酸反应持续存在。hFTF激活hASBT但不激活mASBT，而mLRH-1激活mASBT但不激活hASBT。siFTF降低hASBT活性但不降低mASBT活性；siLRH降低mASBT活性但不降低hASBT活性。siLRH而非siFTF消除了胆汁酸反应性。电泳迁移率变动分析证明mLRH-1或hFTF顺式作用元件存在独特且特异性的结合。总之，FTF和LRH-1是人类Caco-2细胞中两个相关但不同的转录因子，表明它们可能是同源物而非直系同源物。FTF不直接参与胆汁酸介导的ASBT负反馈调节。
