从AhR和PPARs调控失衡探讨持久有机污染物暴露致胰岛素抵抗的机制及化浊解毒方的干预

It has been demonstrated that Persistent organic pollutants (POPs) exposure works as an important factor in the occurrence of insulin resistance (IR). POPs can specifically activate the aryl hydrocarbon receptor (AhR), independently interfere glucose and lipid metabolism, stimulate the inflammatory response and lead to IR. PPARs is a key element for stabilizing glucose and lipid metabolism homeostasis which plays an important role in IR. However, recent studies have shown that AhR also affects the expression of PPARs, and there are multiple coincident targets on the downstream. It is obvious that POPs exposure leads to the interaction of AhR and PPARs in IR. Based on these fact, we put forward a hypothesis that "in the condition of POPs exposure, AhR and regulation of PPARs will imbalance on glucose and lipid metabolism, and stimulate the inflammatory to response and finally lead to IR". The previous studies have shown that Huazhuo Jiedu decoction can improve glucose and lipid metabolism in IR intervention, and natural compounds have been found to work as a AhR antagonist. Therefore, this project aims to establish IR model of POPs exposure, with Huazhuo Jiedu prescription intervention, through the observation of AhR and PPARs and the expression of POPs on downstream targets, we can make clear statement on the exposure to IR mechanism, clarify the effect of Huazhuo Jiedu recipe IR intervention, and explore its possible mechanism. This study is helpful to provide clues for the prevention and treatment of POPs exposure and explain the scientific connotation of "Waiduneixu“。

持久性有机污染物（POPs）暴露作为胰岛素抵抗（IR）发生的重要因素已得到证实。POPs能特异性激活芳香烃受体（AhR），独立干预糖脂代谢、激发炎症反应进而导致IR。PPARs是糖脂代谢稳态的关键点在IR中有重要作用。然而，最新研究表明，AhR还影响PPARs表达，且两者下游有多个重合靶点。可见POPs暴露导致IR是AhR和PPARs的共同作用。基于此，我们提出“POPs暴露下AhR和PPARs调控失衡影响糖脂代谢、激发炎症反应进而导致IR”的假说，前期研究表明，化浊解毒方能干预糖脂代谢改善IR；且其单味药所含天然化合物已发现有"AhR拮抗剂"作用。故本项目拟建立POPs染毒IR模型，以化浊解毒方干预，通过观察AhR和PPARs及下游靶点表达，明确POPs暴露致IR机制；并阐明化浊解毒方干预IR的效应，进而探讨其可能机制。本研究有助于为防治POPs暴露致IR提供线索和阐释“外毒内蓄“内涵。

持久性有机污染物（Persistent Organic Pollutants，POPs）作为人类合成的一类理化性质稳定、难降解、高脂溶性、高蓄积性的环境污染物，作为胰岛素抵抗和糖尿病发生发展重要因素已经得到证实。POPs能特异性激活芳香烃受体（AhR），独立干预糖脂代谢、激发炎症反应进而导致IR。AhR还影响PPARs表达，且两者下游有多个重合靶点。可见POPs暴露导致IR是AhR和PPARs的共同作用。基于此我们提出“POPs暴露下AhR和PPARs调控失衡影响糖脂代谢、激发炎症反应进而导致IR”的假说。中医“浊毒”理论与其有类似之处，“浊毒”理论认为“食物、饮水以及环境等毒素可经口鼻、肌肤入侵体内，造成外毒内伏渐蓄而成内毒即外毒内蓄”。化浊解毒方对胰岛素抵抗具有较好的临床疗效。我们应用此方干预POPS染毒的大鼠和HepG2细胞，探讨其调控作用及可能的机制，PCB126暴露经化浊解毒方处理后，给药大鼠肝脏组织及脂肪组织以及HepG2细胞的AhRmRNA水平及蛋白表达水平降低，与IR相关的糖脂代谢指标、炎症基因TNFα及CD36mRNA水平及蛋白表达水平较染毒组降低，具有改善糖脂毒性、增加胰岛素敏感性的PPARα、PPARγ、GLUT4及FGF21的mRNA水平及蛋白表达水平升高，胰岛素抵抗指数降低，说明化浊解毒方具有改善PCB126暴露糖脂毒性及胰岛素抵抗的作用，机制可能与其干预AhR/PPARs的表达，进而影响下游CD36、TNFα、GLUT4及FGF21的表达有关。化浊解毒方显示出与阳性药CH223191同等的效果，且呈现一定的量效关系，说明此方具有类“AhR受体拮抗剂”的作用。因此，化浊解毒方对进入体内的“环境污染之毒”同样具有良好的“解毒”功效，其部分机制与其调控AhR与PPARs进而影响下游CD36、TNFα、GLUT4及FGF21的表达有关。