胆汁酸核受体FXR介导的菊三七肝毒性作用机制研究

Herbal medicine induced liver injury has evoked worldwide attention and is now among the most concerned problems about traditional Chinese medicine. Investigation into the pathogenesis of HILI is of great significance for its clinical prevention and treatment but is still a big challenge. Exposure to herbal medinces containing hepatotoxic pyrrolizidine alkaloids (HPAs), such as Gynura Rhizoma, is one of the two major risk factors for inducing hepatic sinusoidal obstruction syndrome (HSOS), which happens worldwide but with dismal survival rates because of unavailable of efficient therapy treatments. Our previous work has revealed that the liver injury caused by Gynura Rhizoma is closely related to the bile acids homeostasis mediated by farnesoid X receptor (FXR). However, no further investigation is carried out to illustrate the underlying mechanism. Therefore, the present project aims to uncover the key role of FXR mediated hepatotoxicity caused by Gynura Rhizoma via studying the down-stream targets and related molecular signaling pathways, such as ERK1/2/MAPK pathway, JNK1/2/c-Jun pathway, and bile acids enteroheptic cycle. The present study will shed new light on the mechanism of HPAs-induced hepatotoxicity, which will fascinate the detoxification of herbal drugs containing HPAs and treatment of HSOS in clinic. The methodology will also provide useful information for the study of herbal drug induced liver injury.

近年来中药导致的药物性肝损伤(HILI)成为国际国内最关注的中药安全性问题之一，深入研究其发病机制对于HILI的临床防治具有重大意义。菊三七等含肝毒性吡咯里西啶生物碱(HPAs)的中草药可导致肝窦阻塞综合征(HSOS)，该疾病在全球范围发生，重症致死率高达90%且尚无有效治疗方案。我们前期研究发现胆汁酸核受体法尼醇X受体(FXR)调控的胆汁酸代谢失衡与菊三七肝毒性密切相关，然而FXR如何介导HPAs肝毒性在国内外均未有深入研究。因此，本课题以FXR调控胆汁酸代谢为切入点，旨在通过研究HPAs肝毒性与FXR调控胆汁酸代谢的下游靶基因及信号通路（ERK1/2/MAPK通路、JNK1/2/c-Jun通路、胆汁酸代谢通路）之间的关系，揭示FXR在菊三七肝毒性的作用，阐明HPAs肝毒性的新机制，为此类中药减毒策略的开发及临床HSOS疾病的治疗提供科学依据，为中药药物性肝损伤的基础和应用研究提供借鉴。

在国家自然科学基金的资助下，本课题以肝毒性吡咯里西啶生物碱(HPAs)为研究对象，针对菊三七等中药导致药源性肝损伤(HILI)的机制研究不足，结合课题组前期研究基础，探讨FXR调控胆汁酸代谢致菊三七肝毒性的研究。解决了以下重要问题：(1) 建立了稳定可重复的符合临床病理的菊三七致SOS小鼠模型，为该类中草药毒性机制和减毒策略的研究提供研究模型；(2) 发现PA致胆汁酸代谢失调在SOS患者和小鼠中的一致性,为基于胆汁酸代谢研究临床SOS的研究提供研究方法；(3) 发现PAs可结合于FXR-LBD蛋白抑制FXR的表达和活性, 从而调控下游靶基因，造成胆汁酸肝内淤积致毒，为PA致临床SOS治疗药物研发提供新的靶点；(4) 建立了FXR配体的体外快速筛选平台,并发现了常用保肝利胆中药胆宁片、熊胆粉、泽泻FXR的天然配体。本项目为中药药源性肝损伤的研究提供了方法学示范。发表论文7篇，培养博士生1名、硕士生2名。