PCBs组织特异性调节AhR/Nrf2诱发氧化还原稳态失衡导致糖脂代谢紊乱的分子机制

多氯联苯（PCBs）暴露与糖脂代谢紊乱密切相关，然而，其具体致病机制不清。我们的前期研究发现，PCB-153组织特异性调节多环芳烃受体（AhR），抑制Nrf2-抗氧化酶链，提示AhR通过调节Nrf2诱发氧化还原稳态失衡，可能是PCBs导致糖脂代谢紊乱的关键。我们提出科学设想：PCBs组织特异性调节AhR信号通路，抑制Nrf2-抗氧化酶链，诱发氧化还原稳态失衡，影响脂肪分化和脂解过程，最终导致糖脂代谢紊乱。为证明该设想，本项目拟从典型PCBs入手，利用组织特异性过表达或敲减AhR/Nrf2小鼠与慢病毒转染细胞，研究AhR/Nrf2相互作用影响氧化还原平衡和糖脂代谢的机制，并重点研究PCBs通过AhR/Nrf2调控脂肪分化与脂解的分子机制。明确AhR/Nrf2组织特异性调节氧化还原稳态在PCBs导致糖脂代谢紊乱中的关键作用和机制，为认识其致病机制及制定防治策略提供理论和实验依据。

Polychlorinated biphenyls (PCBs) exposure is believed to be closely associated with the disorder of glucose/lipid metabolism. However, the molecular mechanism is unclear. Our preliminary results showed that PCB-153 tissue-specifically regulated aryl hydrocarbon receptor (AhR) and inhibited nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant enzyme chain, resulting in glucose/lipid metabolic disorder. The results demonstrated that AhR-mediated regulation of Nrf2 and subsequent disturbance of redox homeostasis may be the key step toward PCBs-induced disorder of glucose/lipid metabolism. Based on our previous results and literature, we propose a scientific hypothesis: in the background of genetic sensitivity, PCBs tissue-specifically regulates AhR signaling pathway, inhibits Nrf2-antioxidant enzyme chain, disturbs redox homeostasis, and affects adipocyte differentiation and lipolysis, leading to glucose/lipid metabolic disorder. To verify the hypothesis, in the present project, using animal model of tissue-specific AhR/Nrf2 knock down/up and cells transfected with lentivirus, we will focus on PCB-126 and PCB-153 and (1) study the effect of AhR/Nrf2 interaction on glucose/lipid metabolism and redox homeostasis; (2) further elucidate the molecular mechanism underlying role of AhR/Nrf2 interaction in PCBs-induced effect on adipogenesis and lipolysis. After all these experiments, we expect to elucidate the key role of tissue-specific regulation of redox homeostasis by AhR/Nrf2 interaction and provide theoretical and practical evidence for the insight into the pathogenesis and preventive strategy of PCBs-induced glucose/lipid metabolic disorder.