Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
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DOI：
10.1093/toxsci/kfv245
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发表时间：
2016-02-01
影响因子：
3.8
通讯作者：
Zacharewski, Timothy R.
中科院分区：
文献类型：
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作者：
Nault, Rance;Fader, Kelly A.;Zacharewski, Timothy R.
环境污染物2，3，7，8-四氯二苯并-对-二恶英（TCDD）导致剂量依赖性肝毒性，包括脂肪蓄积、炎症和纤维化，其可进展为肝细胞癌。为了进一步研究这些影响，将RNA-Seq数据与计算确定的推定二恶英反应元件以及来自雌性C57 BL/6小鼠的互补靶向代谢组学和芳烃受体（AhR）ChIP-Seq数据整合，雌性C57 BL/6小鼠每4天灌胃一次TCDD，持续28天。使用CytoKEGG与手动管理的数据整合确定了中心碳和氨基酸代谢的剂量依赖性改变。更具体地说，TCDD增加丙酮酸激酶亚型M2（PKM 2）基因和蛋白质的表达。PKM 2具有较低的催化活性，导致糖酵解通量降低和上游中间体的积累，所述上游中间体被重定向到磷酸戊糖途径和丝氨酸/叶酸生物合成，这两个重要的NADPH产生途径源自糖酵解。此外，GAC：KGA转氨酶（GLS 1）蛋白亚型比例增加，这与对TCA循环起回补作用并补偿糖酵解通量减少的精氨酸水解增加一致。总的来说，基因表达，蛋白质和代谢产物的变化表明NADPH生产的增加，支持细胞色素P450活性和ROS防御。这种AhR介导的代谢重编程类似于瓦尔堡效应，代表了一种新的有利的防御机制，以增加正常分化肝细胞的抗氧化能力。
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits dose-dependent hepatotoxicity that includes fat accumulation, inflammation, and fibrosis that may progress to hepatocellular carcinoma. To further investigate these effects, RNA-Seq data were integrated with computationally identified putative dioxin response elements, and complementary targeted metabolomic and aryl hydrocarbon receptor (AhR) ChIP-Seq data from female C57BL/6 mice gavaged with TCDD every 4 days for 28 days. Data integration using CytoKEGG with manual curation identified dose-dependent alterations in central carbon and amino acid metabolism. More specifically, TCDD increased pyruvate kinase isoform M2 (PKM2) gene and protein expression. PKM2 has lower catalytic activity resulting in decreased glycolytic flux and the accumulation of upstream intermediates that were redirected to the pentose phosphate pathway and serine/folate biosynthesis, 2 important NADPH producing pathways stemming from glycolysis. In addition, the GAC:KGA glutaminase (GLS1) protein isoform ratio was increased, consistent with increases in glutaminolysis which serves an anaplerotic role for the TCA cycle and compensates for the reduced glycolytic flux. Collectively, gene expression, protein, and metabolite changes were indicative of increases in NADPH production in support of cytochrome P450 activity and ROS defenses. This AhR-mediated metabolic reprogramming is similar to the Warburg effect and represents a novel advantageous defense mechanism to increase anti-oxidant capacity in normal differentiated hepatocytes.