Suppression of sterol 12α-hydroxylase transcription by the short heterodimer partner:: insights into the repression mechanism
Suppression of sterol 12α-hydroxylase transcription by the short heterodimer partner:: insights into the repression mechanism
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DOI：
10.1093/nar/29.19.4035
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发表时间：
2001-10-01
影响因子：
14.9
通讯作者：
Gil, G
中科院分区：
文献类型：
--
作者：
del Castillo-Olivares, A;Gil, G
胆固醇转化为胆汁酸受反馈调节机制的影响，胆汁酸下调其自身的合成。这种调控发生在胆汁酸生物合成途径中编码酶的几个基因的转录水平上。其中一种酶是甾醇12 α -羟化酶/CYP8B1 （12 α -羟化酶），这是合成胆酸所需的特殊酶。这种酶的水平决定了胆酸与鹅去氧胆酸的比例，从而决定了循环胆汁酸池的疏水性。该实验室先前的研究表明，胎儿蛋白转录因子（FTF）是12 α -羟化酶启动子活性和胆汁酸介导的调节所必需的。在这里，我们报道了短异二聚体伴侣（SHP）通过与FTF的相互作用抑制12 α -羟化酶启动子活性。肝核因子-4 （HNF-4）结合并激活12 α -羟化酶启动子，是12 α -羟化酶启动子活性所必需的。虽然HNF-4与SHP相互作用，但它不参与SHP介导的12 α -羟化酶启动子活性的抑制。FTF而非HNF-4是胆汁酸通过与SHP相互作用调节12 α -羟化酶启动子活性的因子。最后，SHP与FTF的相互作用取代了FTF与12 α -羟化酶启动子内的位点的结合。这些结果为胆汁酸介导的甾醇12a-羟化酶转录调控的作用机制提供了见解。
Cholesterol conversion to bile acids is subject to a feedback regulatory mechanism by which bile acids down-regulate their own synthesis. This regulation occurs at the level of transcription of several genes encoding enzymes in the bile acid biosynthetic pathway. One of these enzymes is sterol 12 alpha -hydroxylase/CYP8B1 (12 alpha -hydroxylase), the specific enzyme required for cholic acid synthesis. The levels of this enzyme determine the ratio of cholic acid to chenodeoxycholic acid and thus the hydrophobicity of the circulating bile acid pool. Previous studies from this laboratory showed that fetoprotein transcription factor (FTF) is required for 12 alpha -hydroxylase promoter activity and bile acid-mediated regulation. Here, we report that the short heterodimer partner (SHP) suppresses 12 alpha -hydroxylase promoter activity via an interaction with FTF. Hepatic nuclear factor-4 (HNF-4) binds and activates the 12 alpha -hydroxylase promoter and is required for 12 alpha -hydroxylase promoter activity. Although HNF-4 interacts with SHP, it is not involved in SHP-mediated suppression of 12 alpha -hydroxylase promoter activity. FTF and not HNF-4 is the factor involved in regulation of 12 alpha -hydroxylase promoter activity by bile acids through its interaction with SHP. Finally, interaction of SHP with FTF displaces FTF binding to its sites within the 12 alpha -hydroxylase promoter. These results provide insights into the mechanism of action of bile acid-mediated regulation of sterol 12a-hydroxylase transcription.