Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.
Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.
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DOI：
10.1093/toxsci/kfv250
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发表时间：
2016-02
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影响因子：
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通讯作者：
B. Wahlang;R. Prough;K. Falkner;Josiah E. Hardesty;Ming Song;Heather B. Clair;B. Clark;J. States;G. Arteel;M. Cave
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文献类型：
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作者：
B. Wahlang;R. Prough;K. Falkner;Josiah E. Hardesty;Ming Song;Heather B. Clair;B. Clark;J. States;G. Arteel;M. Cave
多氯联苯（PCBs）是与非酒精性脂肪性肝炎（NASH）、糖尿病和肥胖症相关的环境污染物。我们以前证明，PCB混合物，Aroclor 1260，诱导脂肪性肝炎和激活核受体在饮食诱导的肥胖小鼠模型。本研究旨在评估NASH中PCB与孕烷异生素受体（Pxr：Nr 1 i2）和组成性雄烷受体（Car：Nr 1 i3）的相互作用。在这项为期12周的研究中，野生型C57 Bl/6（WT）、Pxr（-/-）和Car（-/-）小鼠喂食高脂肪饮食（42%乳脂），并暴露于单剂量的Aroclor 1260（20 mg/kg）。进行代谢表型分析和血清、肝脏和脂肪分析。脂肪性肝炎在所有Aroclor暴露组中的病理学相似，而Pxr（-/-）小鼠显示出更高的基础促炎细胞因子水平。Pxr（-/-）小鼠中基础Car/Cyp 2b 10表达增加证明Pxr抑制Car表达。Pxr（-/-）和Car（-/-）小鼠均显示基础呼吸交换率（RER）降低，与优先脂质代谢一致。Aroclor增加RER和碳水化合物代谢，与两种基因敲除小鼠的光周期活性增加有关，并减少Car（-/-）小鼠的摄食量。Aroclor暴露改善WT小鼠的胰岛素敏感性，但不改善葡萄糖耐量。暴露于多氯联苯的Pxr（-/-）小鼠显示出致肿瘤基因表达增加。脂质氧化基因表达在WT和Pxr（-/-）小鼠中较高，但RER没有改变，表明PCB介导的线粒体功能障碍。因此，Pxr和Car在PCB介导的NASH中调节炎症、行为和能量代谢。未来的研究应该解决脂肪性肝炎中多氯联苯的“脱靶”效应。
Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis.