Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Russia.
Eur J Pharmacol. 2012 Mar 15;679(1-3):139-43. doi: 10.1016/j.ejphar.2012.01.007. Epub 2012 Jan 24.
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.
组成型雄烷受体（CAR，NR1I3）在解毒过程中起着核心作用，调节一组参与代谢的基因的表达。NR1I3 作为外源性传感器和内源性能量代谢调节剂的双重作用最近已被接受。在这里，我们研究了顺式 2,4,6-三苯基二恶烷-1,3（cisTPD）对葡萄糖代谢基因磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）的转录调控机制，cisTPD 是大鼠肝脏中一种非常有效的 NR1I3 激活剂。结果表明，在禁食条件下，cisTPD 处理抑制了糖异生基因 PEPCK 和 G6Pase 的表达。Western blot 分析表明，与对照组相比，cisTPD 处理动物肝脏中的 PEPCK 和 G6Pase 免疫条带强度明显降低。染色质免疫沉淀试验表明，cisTPD 阻止 FOXO1 与大鼠肝中 PEPCK 和 G6Pase 基因启动子中的胰岛素反应序列结合。此外，cisTPD 激活的 NR1I3 通过与 NR2A1 竞争结合糖异生基因启动子中的 NR2A1 结合元件（DR1 位点）来抑制 NR2A1（HNF-4）的反式激活。因此，我们的结果与 cisTPD 激活的 NR1I3 参与调节糖异生基因 PEPCK 和 G6Pase 的假说一致。
