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首页> 外文期刊>Molecular and Cellular Biology >Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes
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Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes

机译：核受体CAR和PXR与FOXO1的相互作用可以调节编码药物代谢和糖原生成酶的基因。

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The nuclear receptors CAR and PXR activate hepatic genes in response to therapeutic drugs and xenobiotics, leading to the induction of drug-metabolizing enzymes, such as cytochrome P450. Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes. Induction by drugs is known to be decreased by insulin, whereas gluconeogenic activity is often repressed by treatment with certain drugs, such as phenobarbital (PB). Performing cell-based transfection assays with drug-responsive and insulin-responsive enhancers, glutathione S-transferase pull down, RNA interference (RNAi), and mouse primary hepatocytes, we examined the molecular mechanism by which nuclear receptors and FOXO1 could coordinately regulate both enzyme pathways. FOXO1 was found to be a coactivator to CAR- and PXR-mediated transcription. In contrast, CAR and PXR, acting as corepressors, downregulated FOXO1-mediated transcription in the presence of their activators, such as 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pregnenolone 16α-carbonitrile, respectively. A constitutively active mutant of the insulin-responsive protein kinase Akt, but not the kinase-negative mutant, effectively blocked FOXO1 activity in cell-based assays. Thus, insulin could repress the receptors by activating the Akt-FOXO1 signal, whereas drugs could interfere with FOXO1-mediated transcription by activating CAR and/or PXR. Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car?/? mice. We conclude that FOXO1 and the nuclear receptors reciprocally coregulate their target genes, modulating both drug metabolism and gluconeogenesis.
机译：核受体CAR和PXR响应治疗药物和异种生物而激活肝基因，从而导致诱导药物代谢酶，例如细胞色素P450。胰岛素抑制FOXO1表达编码糖异生酶的基因的能力。已知通过胰岛素可减少药物的诱导，而通过使用某些药物（如苯巴比妥（PB））治疗通常会抑制糖原异生活性。用药物反应性和胰岛素反应性增强剂，谷胱甘肽 S 转移酶下拉，RNA干扰（RNAi）和小鼠原代肝细胞进行基于细胞的转染测定，我们研究了核受体的分子机制FOXO1可以协同调节这两种酶的途径。发现FOXO1是CAR和PXR介导的转录的共激活因子。相比之下，CAR和PXR，在它们的激活剂如1,4-双[2-（3,5-二氯吡啶氧基）]苯（TCPOBOP）和孕烯醇酮16α-腈的存在下，下调了FOXO1介导的转录。 ， 分别。胰岛素反应蛋白激酶Akt的组成型活性突变体，而不是激酶阴性突变体，在基于细胞的测定中有效阻断了FOXO1的活性。因此，胰岛素可以通过激活Akt-FOXO1信号来抑制受体，而药物可以通过激活CAR和/或PXR来干扰FOXO1介导的转录。用TCPOBOP或PB处理可降低小鼠中的磷酸烯醇丙酮酸羧化激酶1 mRNA水平，但不会降低 Car ？/？小鼠。我们得出的结论是，FOXO1和核受体相互调节其靶基因，从而调节药物代谢和糖异生。

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