Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes
Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes
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DOI：
10.1016/j.ejphar.2012.01.007
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发表时间：
2012-03-15
影响因子：
5
通讯作者：
Pustylnyak, Vladimir O.
中科院分区：
文献类型：
--
作者：
Kachaylo, Ekaterina M.;Yarushkin, Andrei A.;Pustylnyak, Vladimir O.
组成型雄甾烷受体（CAR，NR 1 I3）在解毒过程中发挥核心作用，调节一组参与代谢的基因的表达。NR 1 I3作为异种传感器和作为内源性能量代谢调节剂的双重作用最近已被接受。在这里，我们研究了葡萄糖代谢基因磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6磷酸酶）的转录调控机制的顺式异构体的2，4，6-三苯基二氧六环-1，3（cisTPD），一种高效的NR 1 I3激活剂在大鼠肝脏。研究表明，禁食条件下cisTPD处理抑制了糖异生基因PEPCK和G6 Pase的表达。蛋白质印迹分析表明，相对于对照动物肝脏的条带，cisTPD处理动物肝脏的PEPCK和G6 β免疫带的强度明显降低。染色质免疫沉淀试验表明，cisTPD阻止FOXO 1的结合，在大鼠肝脏中的PEPCK和G6 β基因启动子的胰岛素反应序列。此外，顺式TPD激活的NR 1 I3通过与NR 2A 1竞争结合致瘤基因启动子中的NR 2A 1结合元件（DR 1位点）来抑制NR 2A 1（HNF-4）的反式激活。因此，我们的研究结果与cisTPD激活的NR 1 I3参与调节致癌基因PEPCK和G6 β的假设一致。(C)2012爱思唯尔有限公司版权所有。
The constitutive androstane receptor (CAR, NR1I3) has a central role in detoxification processes, regulating the expression of a set of genes involved in metabolism. The dual role of NR1I3 as both a xenosensor and as a regulator of endogenous energy metabolism has recently been accepted. Here, we investigated the mechanism of transcriptional regulation of the glucose metabolising genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by the cis isomer of 2,4,6-triphenyldioxane-1,3 (cisTPD), a highly effective NR1I3 activator in rat liver. It was shown that expression of the gluconeogenic genes PEPCK and G6Pase was repressed by cisTPD treatment under fasting conditions. Western-blot analysis demonstrated a clear reduction in the intensity of PEPCK and G6Pase immunobands from the livers of cisTPD-treated animals relative to bands from the livers of control animals. Chromatin immunoprecipitation assays demonstrated that cisTPD prevents the binding of FOXO1 to the insulin response sequences in the PEPCK and G6Pase gene promoters in rat liver. Moreover, cisTPD-activated NR1I3 inhibited NR2A1 (HNF-4) transactivation by competing with NR2A1 for binding to the NR2A1-binding element (DR1-site) in the gluconeogenic gene promoters. Thus, our results are consistent with the hypothesis that the cisTPD-activated NR1I3 participates in the regulation of the gluconeogenic genes PEPCK and G6Pase. (C) 2012 Elsevier B.V. All rights reserved.