Polychlorinated biphenyls-153 induces metabolic dysfunction through activation of ROS/NF-κB signaling via downregulation of HNF1b.
Polychlorinated biphenyls-153 induces metabolic dysfunction through activation of ROS/NF-κB signaling via downregulation of HNF1b.
复制标题
多氯联苯 153 通过下调 HNF1b 激活 ROS/NF-kappa B 信号传导诱导代谢功能障碍
DOI：
10.1016/j.redox.2017.02.026
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wu H;Yu W;Meng F;Mi J;Peng J;Liu J;Zhang X;Hai C;Wang X
多氯联苯 (PCB) 是持久性有机污染物 (POP) 的主要类型，是内分泌干扰化学品。在当前的研究中，我们研究了 PCB-153 对体内和体外葡萄糖和脂质代谢影响的机制。我们发现 PCB-153 本身会诱导并恶化高脂肪饮食 (HFD) 导致的血糖水平升高以及葡萄糖和胰岛素不耐受。此外，PCB-153 本身会诱导并恶化 HFD 导致的甘油三酯含量和脂肪量的增加。此外，PCB-153浓度依赖性地抑制培养的肝细胞和脂肪细胞中胰岛素依赖性的葡萄糖摄取和脂质积累。 PCB-153诱导p65 NF-κB的表达和核转位及其下游炎症标志物的表达，并加剧HFD导致的这些炎症标志物的增加。抑制 NF-κB 可显着抑制 PCB-153 诱导的炎症、脂质积累和葡萄糖摄取减少。 PCB-153 在体内和体外诱导氧化应激并降低肝细胞核因子 1b (HNF1b) 和谷胱甘肽过氧化物酶 1 (GPx1) 表达。 HNF1b的过表达增加了GPx1的表达，降低了ROS水平，降低了Srebp1、ACC和FAS的表达，并抑制了PCB-153导致的氧化应激、NF-κB介导的炎症和最终的葡萄糖/脂质代谢紊乱。我们的结果表明，HNF1b/ROS/NF-κB 的失调在 PCB-153 诱导的葡萄糖/脂质代谢紊乱中起着重要作用。
Polychlorinated biphenyls (PCB) is a major type of persistent organic pollutants (POPs) that act as endocrine-disrupting chemicals. In the current study, we examined the mechanism underlying the effect of PCB-153 on glucose and lipid metabolism in vivo and in vitro. We found that PCB-153 induced per se and worsened high fat diet (HFD)-resulted increase of blood glucose level and glucose and insulin intolerance. In addition, PCB-153 induced per se and worsened HFD-resulted increase of triglyceride content and adipose mass. Moreover, PCB-153 concentration-dependently inhibited insulin-dependent glucose uptake and lipid accumulation in cultured hepatocytes and adipocytes. PCB-153 induced the expression and nuclear translocation of p65 NF-κB and the expression of its downstream inflammatory markers, and worsened HFD-resulted increase of those inflammatory markers. Inhibition of NF-κB significantly suppressed PCB-153-induced inflammation, lipid accumulation and decrease of glucose uptake. PCB-153 induced oxidative stress and decreased hepatocyte nuclear factor 1b (HNF1b) and glutathione peroxidase 1 (GPx1) expression in vivo and in vitro. Overexpression of HNF1b increased GPx1 expression, decreased ROS level, decreased Srebp1, ACC and FAS expression, and inhibited PCB-153-resulted oxidative stress, NF-κB-mediated inflammation, and final glucose/lipid metabolic disorder. Our results suggest that dysregulation of HNF1b/ROS/NF-κB plays an important role in PCB-153-induced glucose/lipid metabolic disorder.