Combining Genomics To Identify the Pathways of Post-Transcriptional Nongenotoxic Signaling and Energy Homeostasis in Livers of Rats Treated with the Pregnane X Receptor Agonist, Pregnenolone Carbonitrile,Journal of Proteome Research

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Combining Genomics To Identify the Pathways of Post-Transcriptional Nongenotoxic Signaling and Energy Homeostasis in Livers of Rats Treated with the Pregnane X Receptor Agonist, Pregnenolone Carbonitrile
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-09-06 00:00:00 , DOI: 10.1021/acs.jproteome.7b00364
Hirohisa Nagahori ₁ , Kenji Nakamura , Kayo Sumida ₁ , Shingo Ito , Sumio Ohtsuki

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Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile (PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant, membrane, and cytosolic fractions of enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchronous increase in mRNAs and proteins involved in chemical carcinogenesis and the response to drug was possibly mediated by the PXR pathway and proteasome core complex assembly was possibly mediated by the Nrf2 pathway. In addition, levels of proteins in the endoplasmic reticulum lumen and involved in the acute-phase response showed specific increase with no change in mRNA level, and those composed of the mitochondrial inner membrane showed specific decrease. The analysis of phosphorylated peptides of poly(A) RNA binding proteins showed a decrease in phosphorylation, possibly by casein kinase 2, which may be related to the regulation of protein expression. Proteins involved in insulin signaling pathways showed an increase in phosphorylation, possibly by protein kinase A, and those involved in apoptosis showed a decrease. Metabolomic analysis suggested the activation of the pentose phosphate and anaerobic glycolysis pathways and the increase of amino acid and fatty acid levels, as occurs in the Warburg effect. In conclusion, the results of combined analyses suggest that PXR’s effects are due to transcriptional and post-transcriptional regulation with alteration of nongenotoxic signaling pathways and energy homeostasis.

中文翻译：

结合基因组学，以鉴定孕烷X受体激动剂孕烯醇酮甲腈治疗的大鼠肝脏转录后非基因毒性信号传导和能量稳态。

将大鼠反复口服PXR激动剂孕烯醇酮碳腈（PCN）7天后，结合转录组学，蛋白质组学，磷酸化蛋白质组学和代谢组学分析来确定孕烷X受体（PXR）在肝脏的非遗传毒性信号传导和能量稳态中的作用。放大的肝匀浆的上清液，膜和胞浆级分中的mRNA和蛋白质的分析显示出多种表达谱。基因集富集分析表明，与化学致癌作用有关的mRNA和蛋白质的同步增加和对药物的反应可能是由PXR途径介导的，而蛋白酶体核心复合物组装可能是由Nrf2途径介导的。此外，内质网管腔中蛋白的水平和参与急性期反应的蛋白水平显示特异性增加，而mRNA水平没有变化，而由线粒体内膜组成的蛋白水平显示特异性降低。聚（A）RNA结合蛋白的磷酸化肽的分析表明磷酸化的减少，可能是酪蛋白激酶2的减少，这可能与蛋白质表达的调节有关。参与胰岛素信号传导途径的蛋白质可能通过蛋白激酶A磷酸化增加，而参与细胞凋亡的蛋白质则减少。代谢组学分析表明磷酸戊糖的活化和厌氧糖酵解途径的活化以及氨基酸和脂肪酸水平的增加，如在Warburg效应中所发生的那样。综上所述，

更新日期：2017-09-07

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