Wu Hao, Yu Weihua, Meng Fansen, Mi Jie, Peng Jie, Liu Jiangzheng, Zhang Xiaodi, Hai Chunxu, Wang Xin
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Redox Biol. 2017 Aug;12:300-310. doi: 10.1016/j.redox.2017.02.026. Epub 2017 Mar 7.
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.
多氯联苯（PCB）是一类主要的持久性有机污染物（POPs），具有内分泌干扰特性。在本研究中，我们探究了PCB - 153在体内和体外对葡萄糖及脂质代谢产生影响的潜在机制。我们发现，PCB - 153本身会诱导并加剧高脂饮食（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本身会诱导并加剧HFD导致的甘油三酯含量增加和脂肪量增加。而且，PCB - 153在培养的肝细胞和脂肪细胞中呈浓度依赖性地抑制胰岛素依赖的葡萄糖摄取和脂质积累。PCB - 153诱导p65核因子κB（NF -κB）的表达及其核转位以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可显著抑制PCB - 153诱导的炎症、脂质积累以及葡萄糖摄取的减少。PCB - 153在体内和体外均诱导氧化应激，并降低肝细胞核因子1β（HNF1β）和谷胱甘肽过氧化物酶1（GPx1）的表达。过表达HNF1β可增加GPx1的表达、降低活性氧（ROS）水平、降低固醇调节元件结合蛋白1（Srebp1）、乙酰辅酶A羧化酶（ACC）和脂肪酸合酶（FAS）的表达，并抑制PCB - 153导致的氧化应激、NF -κB介导的炎症以及最终的葡萄糖/脂质代谢紊乱。我们的研究结果表明，HNF1β/ROS/NF -κB的失调在PCB - 153诱导的葡萄糖/脂质代谢紊乱中起重要作用。
