Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1
Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1
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DOI：
10.1074/jbc.m314322200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Fukamizu, A
中科院分区：
文献类型：
--
作者：
Yamagata, K;Daitoku, H;Fukamizu, A
胆汁酸的稳态受到反馈机制的严格控制，在反馈机制中，一个非典型的孤儿核受体(NR)小异二聚体伙伴(SHP)失活几个NRs，如肝脏受体同系物-1和肝细胞核因子4。尽管NRs参与了糖异生基因的转录调控，但胆汁酸对糖异生基因表达的影响尚不清楚。在这里，我们报告胆汁酸抑制糖异生基因的表达，包括葡萄糖-6-磷酸酶(G6Pase)、磷酸烯醇式丙酮酸羧激酶和果糖1，6-双磷酸酶，这种方式依赖于SHP。胆酸饮食降低了这些糖异生酶的mRNA水平，而SHP则增加了这些糖异生酶的mRNA水平。报告分析表明，鹅去氧胆酸和转基因SHP可下调肝细胞核因子4介导的磷酸烯醇式丙酮酸羧酸激酶和果糖1，6-双磷酸酶或叉状转录因子Foxo1介导的G6Pase的启动子活性。值得注意的是，Foxo1在体内和体外都与SHP相互作用，导致Foxo1通过竞争共激活cAMP反应元件结合蛋白来抑制Foxo1介导的G6Pase转录。这些发现揭示了一种新的机制，胆汁酸通过依赖于SHP的调节途径来调节糖异生基因的表达。
Bile acid homeostasis is tightly controlled by the feedback mechanism in which an atypical orphan nuclear receptor (NR) small heterodimer partner (SHP) inactivates several NRs such as liver receptor homologue-1 and hepatocyte nuclear factor 4. Although NRs have been implicated in the transcriptional regulation of gluconeogenic genes, the effect of bile acids on gluconeogenic gene expression remained unknown. Here, we report that bile acids inhibit the expression of gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase, and fructose 1,6-bis phosphatase in an SHP-dependent fashion. Cholic acid diet decreased the mRNA levels of these gluconeogenic enzymes, whereas those of SHP were increased. Reporter assays demonstrated that the promoter activity of phosphoenolpyruvate carboxykinase and fructose 1,6-bis phosphatase via hepatocyte nuclear factor 4, or that of G6Pase via the forkhead transcription factor Foxo1, was down-regulated by treatment with chenodeoxicholic acid and with transfected SHP. Remarkably, Foxo1 interacted with SHP in vivo and in vitro, which led to the repression of Foxo1-mediated G6Pase transcription by competition with a coactivator cAMP response element-binding protein-binding protein. These findings reveal a novel mechanism by which bile acids regulate gluconeogenic gene expression via an SHP-dependent regulatory pathway.