Inhibitory Effect of the Small Heterodimer Partner on Hepatocyte Nuclear Factor-4 Mediates Bile Acid-induced Repression of the Human Angiotensinogen Gene*
Inhibitory Effect of the Small Heterodimer Partner on Hepatocyte Nuclear Factor-4 Mediates Bile Acid-induced Repression of the Human Angiotensinogen Gene*
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DOI：
10.1074/jbc.m310577200
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发表时间：
2004-02
影响因子：
4.8
通讯作者：
Yoko Shimamoto;J. Ishida;K. Yamagata;Tomoko Saito;Hideki Kato;Toshiki Matsuoka;K. Hirota;H. Daitoku;M. Nangaku;K. Yamagata;H. Fujii;J. Takeda;A. Fukamizu
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文献类型：
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作者：
Yoko Shimamoto;J. Ishida;K. Yamagata;Tomoko Saito;Hideki Kato;Toshiki Matsuoka;K. Hirota;H. Daitoku;M. Nangaku;K. Yamagata;H. Fujii;J. Takeda;A. Fukamizu
胆汁酸作为胆汁酸合成和胆固醇稳态中重要基因的转录调节因子发挥作用。在这项研究中，我们确定了血管紧张素原（ANG），血管活性八肽血管紧张素II的前体，作为一个新的靶基因的胆汁酸。在人ANG转基因小鼠中，胆酸的施用导致肝脏中人ANG基因表达的下调。鹅去氧胆酸可抑制HepG 2细胞ANG基因的表达。由于鹅去氧胆酸可诱导HepG 2细胞中小异源二聚体伴侣（small heterodimer partner，SHP）mRNA的表达，因此我们分析了SHP对人ANG启动子的影响。启动子突变分析表明，SHP抑制人ANG启动子活性通过元件，这已被确定为肝细胞核因子-4（HNF-4）的结合位点。只有当HNF-4表达载体共转染HeLa细胞时，SHP才能抑制人ANG启动子的活性。此外，我们发现SHP结合到HNF-4的N-末端区域，包括DNA结合结构域和激活功能-1，并且SHP阻止HNF-4与人ANG启动子结合。这些结果表明，胆汁酸通过SHP对HNF-4的抑制作用负调节人ANG基因。
Bile acids function as transcriptional regulators for the genes important in bile acid synthesis and cholesterol homeostasis. In this study, we identified angiotensinogen (ANG), the precursor of vasoactive octapeptide angiotensin II, as a novel target gene of bile acids. In human ANG transgenic mice, administration of cholic acid resulted in the down-regulation of human ANG gene expression in the liver. ANG gene expression in HepG2 cells was also repressed by chenodeoxycholic acid. Because the expression of small heterodimer partner (SHP) mRNA was induced by chenodeoxycholic acid in HepG2 cells, we analyzed the effects of SHP on the human ANG promoter. Promoter mutation analysis demonstrated that SHP repressed human ANG promoter activity through the element, which has been previously determined as a binding site for hepatocyte nuclear factor-4 (HNF-4). SHP repressed human ANG promoter activity only when the HNF-4 expression vector was cotransfected in HeLa cells. Furthermore, we found that SHP bound to the HNF-4 N-terminal region including the DNA-binding domain and activation function-1 and that SHP prevented HNF-4 from binding to the human ANG promoter. These results suggest that bile acids negatively regulate the human ANG gene through the inhibitory effect of SHP on HNF-4.