Metabolic reprogramming by the pyruvate kinase M2 isoform is associated with cell proliferation and reactive oxygen species (ROS) defenses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant that induces ROS and hepatotoxicity, dose-dependently induces pyruvate kinase muscle isoform M2 (PKM2) in the liver. To further investigate its role in combating TCDD hepatotoxicity, a PkmΔDRE mouse was constructed lacking the dioxin response element mediating aryl hydrocarbon receptor (AHR) induction. TCDD failed to induce hepatic PKM2 in PkmΔDRE mice and in primary hepatocytes isolated from an AHR knockout model (AHRV375Afl/flAlb-CreERT2), demonstrating induction is AHR dependent. Both wild-type (WT) and PkmΔDRE mice exhibited dose-dependent increases in liver weight after treatment with TCDD every 4 days for 28 days. Glutathione (GSH) levels increased in WT mice while oxidized glutathione (GSSG) levels increased in both models with a 24-fold decrease in the GSH/GSSG ratio in PkmΔDRE mice suggesting lower antioxidant and recycling capacity. Moreover, TCDD-induced fibrosis was more severe in PkmΔDRE mice while PkmΔDRE hepatocytes exhibited greater cytotoxicity following co-treatment with TCDD and hydrogen peroxide. TCDD also induced PKM2 in human HepaRG™ cells with AHR enrichment at a conserved DRE core within the locus. These results suggest AHR-mediated PKM2 induction is a novel antioxidant response to TCDD.

中文翻译：

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干扰 AHR 介导的肝细胞 PKM2 表达的经典诱导会损害抗氧化防御并增加 TCDD 诱导的肝毒性


丙酮酸激酶 M2 亚型的代谢重编程与细胞增殖和活性氧 （ROS） 防御有关。2,3,7,8-四氯二苯并-对二恶英 （TCDD） 是一种诱导 ROS 和肝毒性的环境污染物，剂量依赖性地诱导肝脏中的丙酮酸激酶肌肉亚型 M2 （PKM2）。为了进一步研究其在对抗 TCDD 肝毒性中的作用，构建了一只缺乏介导芳烃受体 （AHR） 诱导的二恶英反应元件的 PkmΔDRE 小鼠。TCDD 未能在 PkmΔDRE 小鼠和从 AHR 敲除模型 （AHRV375Afl/flAlb-CreERT2） 分离的原代肝细胞中诱导肝脏 PKM2，表明诱导是 AHR 依赖性的。野生型 （WT） 和 PkmΔDRE 小鼠在每 4 天接受 TCDD 治疗后，持续 28 天，肝脏重量均表现出剂量依赖性增加。WT 小鼠的谷胱甘肽 （GSH） 水平升高，而氧化谷胱甘肽 （GSSG） 水平在两种模型中均升高，PkmΔDRE 小鼠的 GSH/GSSG 比率降低 24 倍，表明抗氧化和回收能力较低。此外，TCDD 诱导的纤维化在 PkmΔDRE 小鼠中更为严重，而 PkmΔDRE 肝细胞在与 TCDD 和过氧化氢共同处理后表现出更大的细胞毒性。TCDD 还在人 HepaRG™ 细胞中诱导 PKM2，并在基因座内保守的 DRE 核心处富集 AHR。这些结果表明 AHR 介导的 PKM2 诱导是对 TCDD 的新型抗氧化反应。