JNK/Sab介导的线粒体功能障碍在非酒精性脂肪性肝炎脂毒性肝损伤中的作用及降脂颗粒调控机制研究

The prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing. Based on the pathological mechanism of fatty liver disease “Spleen-Deficiency as the primary cause, Damp-Heat and Blood Stasis as the representation” in traditional Chinese medicine (TCM), the herb formula “Jiangzhi Granule” developed by our study group, has been proved effective in improving fatty liver disease in clinic or animal experiments. Scoparone, one ingredient of Jiangzhi Granule, has also been proofed to have liver-protecting and fat-lowing activity. Mitochondrial dysfunction plays an important role in lipotoxic hepatic injury in NASH, and is closely related to oxidative stress, cell apoptosis and inflammation. JNK/Sab signaling pathway-mediated mitochondrial dysfunction plays key roles in many hepatocyte injury models, including lipotoxic hepatocyte injury model. Therefore, JNK/Sab may become a new therapeutic target for NASH. Our previous study has found the activation of JNK in NASH mice and lipotoxic injury hepatocytes, which can be inhibited after the intervention of Jiangzhi Granule and Scoparone. According to the aforementioned reason, this project plans to investigate the change and role of JNK/Sab signaling pathway with its relative molecules in NASH pathogenesis through in vitro and in vivo experiments. And the study on whether Jiangzhi Granule or its ingredient scoparone could improve NASH through regulating JNK/Sab signaling pathway will also be carried out. This project will help develop new target of diagnosis and therapy for NASH, and discover an alternative therapeutic mechanism of Jiangzhi Granule to provide more scientific basis for its widespread clinic application.

非酒精性脂肪性肝炎（NASH）发病率逐年升高，课题组基于其“脾虚为本，湿热瘀血为标”病机研制的中药复方降脂颗粒在临床及动物试验中均可有效改善脂肪肝，其有效成分滨蒿内酯也具有降脂保肝作用。线粒体功能障碍在NASH脂毒性肝损伤中起重要作用，并与氧化应激、细胞凋亡、炎症反应等密切相关。JNK/Sab信号通路介导的线粒体功能障碍在多种肝细胞损伤模型，包括脂毒性损伤肝细胞模型中起调控作用，可能为NASH治疗新靶点。前期研究发现NASH小鼠及脂毒性损伤肝细胞存在JNK活化，降脂颗粒及其有效成分滨蒿内酯可分别抑制其活化。基于上述，本课题拟通过细胞和动物试验观察JNK/Sab信号通路相关分子在NASH中的变化及作用，以期发现NASH诊疗新靶标，并研究降脂颗粒及其有效成分滨蒿内酯对JNK/Sab信号通路的干预作用，阐述其基于中医药理论治疗NASH的药效机理，为其在临床应用和推广提供科学依据。

非酒精性脂肪性肝炎（NASH）发病率逐年升高，课题组基于其“脾虚为本，湿热淤血为标”病机研制的中药复方降脂颗粒在临床及动物试验中均可有效改善脂肪肝，其有效成分滨蒿内酯也具有降脂保肝作用。线粒体功能障碍在NASH脂毒性肝损伤中起重要作用，并与氧化应激、细胞凋亡、炎症反应等密切相关。JNK/Sab信号通路介导的线粒体功能障碍在多种肝细胞损伤模型，包括脂毒性肝损伤模型中起调控作用，可能为NASH治疗新靶点。前期研究发现NASH小鼠及脂毒性损伤肝细胞存在JNK活化，降脂颗粒及其有效成分滨蒿内酯可分别抑制其活化。本课题通过细胞和动物试验观察JNK/Sab信号通路相关分子在NASH中的变化及作用，并研究降脂颗粒及其有效成分滨蒿内酯对JNK/Sab信号通路的干预作用。研究发现，降脂颗粒、滨蒿内酯能够改善高脂饮食诱导的NASH小鼠体重、肝重、肝酶、血脂、肝脂水平，减轻肝脏炎症损伤，下调炎症因子TNF-α、IL-1β mRN及凋亡蛋白Cleaved PARP的表达，改善线粒体数量及线粒体膜电位，提高mtDNA及线粒体功能相关分子PGC-1α、NRF1、TFAM mRNA水平，同时抑制JNK/Sab信号通路的活化。因此，从目前的研究结果来看，降脂颗粒及其成分滨蒿内酯对NASH脂毒性肝损伤具有防治作用，其机制可能与调控JNK/Sab信号通路介导的线粒体功能障碍有关。此研究结果为促进中医药防治NASH提供了基础及临床参考价值。