DAX-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor HNF4α and Negatively Regulates Gluconeogenic Enzyme Gene Expression
DAX-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor HNF4α and Negatively Regulates Gluconeogenic Enzyme Gene Expression
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DOI：
10.1074/jbc.m109.034660
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发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Choi, Hueng-Sik
中科院分区：
文献类型：
--
作者：
Nedumaran, Balachandar;Hong, Sungpyo;Choi, Hueng-Sik
DAX-1（dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome，gene 1）是核受体家族的一个非典型成员，是许多核受体的辅阻遏物。HNF 4 α（肝细胞核因子4 α）是一种肝脏富集的转录因子，可控制参与胆固醇、脂肪酸和葡萄糖代谢的多种基因的表达。在这里，我们发现DAX-1抑制HNF 4 α的转录活性，并调节肝致凋亡基因的表达。肝脏DAX-1表达增加胰岛素和SIK 1（盐诱导激酶1），而它在高脂肪饮食喂养和糖尿病小鼠中减少。来自小鼠肝脏样品的免疫共沉淀测定显示内源性DAX-1与HNF 4 α在体内相互作用。体内染色质免疫沉淀试验证实，DAX-1在磷酸烯醇式丙酮酸羧激酶（PEPCK）基因启动子上的募集与禁食和再喂养下PGC-1 α和HNF 4 α的募集呈负相关，表明DAX-1可以与辅激活因子PGC-1 α竞争结合HNF 4 α。腺病毒介导的DAX-1表达降低了HNF 4 α和毛喉素介导的致炎基因表达。此外，DAX-1的敲低部分逆转了胰岛素介导的对原代肝细胞中致凋亡基因表达的抑制。最后，DAX-1抑制PEPCK和葡萄糖-6-磷酸酶基因表达，并显着降低高脂饮食喂养的小鼠的空腹血糖水平，表明DAX-1可以调节体内肝脏的新生。总的来说，这项研究表明DAX-1作为HNF 4 α的辅阻遏物，负调控肝脏中的肝致凋亡基因表达。
DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family and acts as a corepressor of a number of nuclear receptors. HNF4 alpha (hepatocyte nuclear factor 4 alpha) is a liver-enriched transcription factor that controls the expression of a variety of genes involved in cholesterol, fatty acid, and glucose metabolism. Here we show that DAX-1 inhibits transcriptional activity of HNF4 alpha and modulates hepatic gluconeogenic gene expression. Hepatic DAX-1 expression is increased by insulin and SIK1 (salt-inducible kinase 1), whereas it is decreased in high fat diet-fed and diabetic mice. Coimmunoprecipitation assay from mouse liver samples depicts that endogenous DAX-1 interacts with HNF4 alpha in vivo. In vivo chromatin immunoprecipitation assay affirms that the recruitment of DAX-1 on the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter is inversely correlated with the recruitment of PGC-1 alpha and HNF4 alpha under fasting and refeeding, showing that DAX-1 could compete with the coactivator PGC-1 alpha for binding to HNF4 alpha. Adenovirus-mediated expression of DAX-1 decreased both HNF4 alpha- and forskolin-mediated gluconeogenic gene expressions. In addition, knockdown of DAX-1 partially reverses the insulin-mediated inhibition of gluconeogenic gene expression in primary hepatocytes. Finally, DAX-1 inhibits PEPCK and glucose-6-phosphatase gene expression and significantly lowers fasting blood glucose level in high fat diet-fed mice, suggesting that DAX-1 can modulate hepatic gluconeogenesis in vivo. Overall, this study demonstrates that DAX-1 acts as a corepressor of HNF4 alpha to negatively regulate hepatic gluconeogenic gene expression in liver.