基于核受体FXR研究芍药苷治疗淤胆型肝炎的生物学机制

As previously supported by the National Natural Science Foundation of China, our research team has proved the therapeutic efficacy and safety of the high-dose of Radix Paeoniae Rubra against cholestatic hepatitis, and found that paeoniflorin (PAE) was the major component in this herb responsible for the effect on relieving jaundice symptom. Preliminary mechanism study showed that PAE can reduce the formation of several kinds of bile acids, and improve the protein expressions of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). Farnesoid X receptor (FXR) exists in the liver and intestine, and plays key role in the metabolism of bile acids and the hepatoprotection. Its activation can regulate the expression of bile acid synthetase, the metabolism and transportation of bile acids. Since PAE improved the protein expression of FXR-regulated bile salt transporters, it is speculated that FXR is the protein target of PAE. The aim of our current study is to investigate the intensive therapeutic mechanisms of PAE against cholestatic hepatitis, its relationship with FXR, and its targeted organ. This study will be performed in liver and intestine primary culture cells and continuous cell lines in vitro and gene knockout cholestatic mice models in vivo through several advanced biological techniques such as luciferase reporter assay, bioinformatics, gene silencing, and targeted metabolomics. This study will provide scientific evidence for PAE as a potential drug candidate for cholestatic hepatitis.

本课题组前期在证实重用赤芍治疗淤胆型肝炎有效性和安全性基础上，发现芍药苷为赤芍中利胆退黄的主要成分，初步机制研究提示芍药苷可调控多种胆汁酸的生成及胆汁转运蛋白如胆盐输出泵和多药耐药相关蛋白2的表达。法尼酯X受体（FXR）主要存在于肝和小肠中，其激活能调控胆汁合成、代谢和转运相关蛋白的表达，在胆汁代谢和肝脏保护中起重要作用。由于芍药苷显著调控FXR受体下游的胆汁转运蛋白，故本课题提出“FXR受体是芍药苷的作用靶点”的工作假说，拟以FXR受体为核心，采用荧光素酶报告基因、生物信息学、基因沉默、靶向代谢组学等研究手段，从体内外不同层面系统考察芍药苷对FXR受体的激活机制，明确芍药苷调控肝/肠中FXR受体上下游信号通路网络及相关效应分子的变化特征，并通过FXR关键蛋白的基因敲除小鼠胆汁淤积模型验证其作用规律。本课题期望通过解析芍药苷利胆退黄的生物学机制，为淤胆型肝炎治疗手段的创新提供理论依据。

本课题组前期在证实重用赤芍治疗淤胆型肝炎有效性和安全性基础上，发现芍药苷为赤芍中利胆退黄的主要成分，初步机制研究提示芍药苷可调控多种胆汁酸的生成及胆汁转运蛋白如胆盐输出泵和多药耐药相关蛋白2的表达。法尼酯X受体（FXR）主要存在于肝和小肠中，其激活能调控胆汁合成、代谢和转运相关蛋白的表达，在胆汁代谢和肝脏保护中起重要作用。但芍药苷是否通过FXR发挥对於胆型肝炎的治疗作用尚不清楚。本研究FXR受体为核心，采用生物信息学、基因沉默、代谢组学等研究手段，明确芍药苷调控肝/肠中FXR受体上下游信号通路网络及相关效应分子的变化特征，系统揭示了芍药苷治疗於胆型肝炎的分子机制。