基于胰高血糖素信号通路的姜黄素调控非酒精性脂肪肝病理状态下内/外源性代谢机制研究

在当今社会高脂高糖的饮食结构下，非酒精性脂肪肝病、肥胖、II型糖尿病等代谢综合症的发病率越来越高。肝脏作为人体最大的代谢解毒器官，参与机体各种内源性物质与外源性异物的代谢，在非酒精性脂肪肝病理状态下肝脏的代谢能力偏离正常，尤其是糖脂代谢异常，一直以来认为其原因主要是胰岛素的作用不足造成，忽略了升糖激素的作用。且非酒精性脂肪肝的治疗一直以来缺乏靶点明确的临床有效药物，姜黄素药效明确，但血药浓度低、作用靶点不明，开发受到限制。本项目以非酒精性脂肪肝为模型，从胰高血糖素的作用入手，分别考察肝保护药物姜黄素与其主要代谢物的分布及其对不同分布位置的内源性物质代谢水平的影响及其作用途径，和对主要药物代谢酶亚型的表达调控。基于代谢组学/通路研究/基因操纵技术等方法对内、外源性代谢通路中各环节的变化进行分析，建立起两者的内在联系，揭示潜在的代谢调控靶标，为临床合理用药和相关药物的研发提供新的思路。

More and more people faced to the metabolic syndrome, including non alcoholic fatty liver disease (NAFLD), obesity, and type II diabetes, because of the high fat and high fructose diet. As the biggest metabolic organ, liver participates in the metabolism of all kinds of endogenous substances and exogenous matters. During NAFLD, the abnormity of the metabolism of glucose and lipids were mainly considered as the results of lack insulin’s action. The importance of glucagon was ignored. Besides, lacking of effective medicines of NAFLD is a big problem. Although curcumin is a potent agent in NAFLD, its low plasma concentration and unclarified target restrained its development. This project is aimed to inspect the distribution of curcumin and its main metabolite and correspondent action on endogenous substances metabolism and drug metabolic enzymes based on NAFLD and glucagon, and to connect endogenous and exogenous substances metabolism according to the results of metabonomics/pathway study/knockout experiments. Further, this project is to reveal potential target of metabolism regulation and provide new idea in related drug development.