基于胆汁酸体内稳态研究慢性心理应激对NASH的促进作用及四逆散的干预机制

近年来临床上发现，慢性心理应激是促进非酒精性脂肪性肝炎（NASH）进展的重要因素。申请人的前期工作提示，机体代谢轮廓响应于慢性心理应激，疏肝中药四逆散的药理活性可能与调控胆汁酸相关信号有关。基于中医学“肝主疏泄”的理论模型，结合文献调研和公共数据库挖掘，提出假说：慢性心理应激可能通过“神经-内分泌-免疫”网络促进NASH，其中胆汁酸体内稳态是此过程的关键环节，也是疏肝解郁代表方剂四逆散的重要靶点。本研究在建立慢性心理应激复合高脂饮食的NASH动物模型的基础上，借助胆汁酸靶向代谢组学、网络药理学等技术，首先确定参与慢性心理应激促进NASH过程的差异胆汁酸种类，其次研究差异胆汁酸对体内体外NASH模型的影响，最后观察四逆散对胆汁酸体内稳态的调控作用。本研究不仅为拓展NASH的发病机制和诊疗思路提供理论依据和实验支撑，还将丰富中医“肝主疏泄”理论模型的科学内涵。

It has been found that chronic psychological stress plays an important role in the progression of non-alcoholic steatohepatitis (NASH) in recent years. The previous study of the applicant revealed that the body's metabolic profiling responds to chronic psychological stress, the pharmacological activity of traditional Chinese medicine (TCM) formula SiNiSan may be related to the regulation of bile acid related signals. Based on the “liver controlling dispersion” theory of TCM, literature investigation and public database mining, it is therefore hypothesized that chronic psychological stress disrupts the bile acid homeostasis in vivo, induces the accumulation of intrahepatic bile acids, thereby promotes the development and progression of NASH; regulating the bile acid homeostasis may be an important target of the pharmacological action of SiNiSan. This study would be based on NASH rat models induced by chronic psychological stress and high fat diet. Firstly, technologies such as targeted metabolomics and network pharmacology would be used to determine the differential bile acids involved in the progression of NASH promoted by chronic psychological stress. Secondly, the effects of differential bile acids on NASH models would be studied in vitro and in vivo. Finally, the regulation of SiNiSan on bile acids homeostasis would be investigated. This study would provide theoretical basis and experimental support for the pathogenesis and treatment of NASH, and would enrich the scientific connotation of the theory of " liver controlling dispersion " in traditional Chinese medicine.