FGF21调控ATF6/eIF2α/CHOP信号通路介导内质网应激肝损伤的分子机制研究

Based on our preliminary clinical findings, hepatic expression of fibroblast growth factor （FGF21）in liver injury patients is significantly reduced, suggesting that FGF21 may serve as a biomarker of pharmacotherapy target. In addition, endoplasmic reticulum stress in liver cells plays a key role in the development of liver injury. However, the association between FGF21 and liver damage-induced endoplasmic reticulum stress has not been reported so far. Therefore, we propose a scientific hypothesis that FGF21 inhibits endoplasmic reticulum stress-regulating and affecting factor activity, thereby modulating hepatocyte survival and alleviating liver disease. In preclinical research, we will use Lentiviral vector-based siRNA technology to specifically knock out FGF21 endogenous expression in hepatocytes in both cell and animal models, and mice models of acute and chronic liver injury were established for screening FGF21 and other regulators expressions. The aim of this study is to investigate the molecular mechanism of FGF21/FIF2α/CHOP signaling pathway in hepatic injury induced by endoplasmic reticulum stress, as well as to study the molecular mechanism involved, contributing to provide a new idea for developing pharmacotherapy and clinical liver injury treatment.

基于前期临床研究发现，各种肝损伤病人肝组织和血清中成纤维细胞生长因子（FGF21）表达显著降低，提示FGF21可能作为肝损伤的潜在生物标记物和治疗靶标。研究表明，肝细胞内质网应激在肝损伤发生发展中具有重要的促发作用。目前，FGF21与内质网应激诱导的肝损伤相关性研究鲜有报道。因此，我们提出科学假说，FGF21通过抑制内质网应激关键调节和效应因子活性，从而调控肝细胞生长而减轻肝损伤病情。在基础研究中，我们采用慢病毒载体siRNA沉默技术在细胞和动物模型中特异性抑制肝细胞FGF21内源性表达，同时构建急性和慢性肝损伤小鼠，阳性和阴性对照模型以检测FGF21及其它关键调控因子活性表达规律。本课题旨在通过现代优势互补的分子生物学方法，较系统地研究FGF21调节因子对内质网应激致肝损伤ATF6/eIF2α/CHOP信号通路的调控效应，并讨论分子作用机制，进而为临床肝损伤治疗和靶向药物研发提供新思路。

研究表明FGF21可能作为肝损伤的潜在生物标记物和治疗靶标。我们开展临床与动物研究表明，功能性FGF21细胞因子可作为VPA 相关肝损伤的有效预测因子。茯苓多糖可能通过抑制细胞死亡，减少肝细胞炎性应激和Hsp90生物活性的分子机制在体内和体外对APAP损伤的肝细胞起到了有益的肝保护作用。生物信息学数据阐明了维生素C的抗肝损伤药理活性可能主要与抑制炎症应激有关，有助于抑制肝损伤的发展。基于比较转录组学和代谢组学分析，我们阐明了维生素 C 抗肝毒性的保护分子机制。 此外，组学分析表明维生素 C 抗肝损伤作用与控制信号网络、抑制亚油酸代谢、减少硫二甘醇酸和提高肝脏中的谷胱甘肽有关。我们通过网络药理学、分子对接和体内初步验证等一系列生物信息学和生化分析，揭示了茯苓多糖抗肝损伤的生物靶点和药理机制。其中通过调控GABRA1、PPARG、ATF6、eIF2α和CHOP活性发挥抑制内质网应激并诱导FGF21活性。此外，我们汇总并开展综述揭示FGF21介导的ATF6/eIF2α/CHOP信号通路在ERS和肝脏功能失调代谢中的作用。