Jiang Yuwei, Xu Jiaoya, Ding Junyao, Liu Tao, Liu Yang, Huang Ping, Wang Qianlei, Zheng Peiyong, Song Haiyan, Yang Lili
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Department of Gout, Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Diabetes Metab Syndr Obes. 2025 Jan 6;18:23-36. doi: 10.2147/DMSO.S492174. eCollection 2025.
Mitochondrial dysfunction mediated by c-Jun N-terminal kinase (JNK) plays an important role in lipotoxic liver injury in nonalcoholic steatohepatitis (NASH). This study aims to investigate the pharmacological mechanism of Jiangzhi Granule (JZG), a Chinese herbal formula against NASH, with a focus on its regulation of JNK signaling-mediated mitochondrial function.
Hepatocytes were induced by palmitic acid (PA) for 24 h to establish an in vitro lipotoxic model, which was simultaneously treated with either JZG or vehicle control. Male C57BL/6J mice were fed a high-fat diet (HFD) for 22 weeks and then treated with JZG via gavage for additional 8 weeks. Lipotoxic injury in hepatocytes or mice liver tissues, as well as JNK signaling-related molecules, were further investigated.
JZG improved PA-induced lipid deposition, cell viability, apoptosis, and mitochondrial dysfunction in hepatocytes. In NASH mice, JZG reduced hepatosteatosis, and inflammatory infiltration, and improved mitochondrial morphology and quantity in liver tissues. Additionally, elevated phosphorylation ratio of non-receptor tyrosine kinase c-Src (Src) and reduced phosphorylation ratio of JNK and SH2-containing protein tyrosine phosphatase (SHP-1) were found in both hepatocytes and mice liver tissues treated with JZG versus those with the vehicle.
Taken together, JZG could improve mitochondrial dysfunction and reduce lipotoxic liver injury in NASH in vivo and in vitro models. The inhibition of the JNK signaling pathway may contribute to the underlying mechanism of JZG in preventing and reversing NASH development.
c-Jun氨基末端激酶（JNK）介导的线粒体功能障碍在非酒精性脂肪性肝炎（NASH）的脂毒性肝损伤中起重要作用。本研究旨在探讨中药方剂降脂颗粒（JZG）抗NASH的药理机制，重点关注其对JNK信号介导的线粒体功能的调节作用。
用棕榈酸（PA）诱导肝细胞24小时以建立体外脂毒性模型，同时用JZG或溶剂对照进行处理。雄性C57BL/6J小鼠喂食高脂饮食（HFD）22周，然后通过灌胃给予JZG额外8周。进一步研究肝细胞或小鼠肝组织中的脂毒性损伤以及与JNK信号相关的分子。
JZG改善了PA诱导的肝细胞脂质沉积、细胞活力、凋亡和线粒体功能障碍。在NASH小鼠中，JZG减少了肝脂肪变性和炎症浸润，并改善了肝组织中的线粒体形态和数量。此外，与溶剂处理组相比，用JZG处理的肝细胞和小鼠肝组织中均发现非受体酪氨酸激酶c-Src（Src）的磷酸化比率升高，而JNK和含SH2结构域的蛋白酪氨酸磷酸酶（SHP-1）的磷酸化比率降低。
综上所述，JZG可改善体内和体外模型中NASH的线粒体功能障碍并减少脂毒性肝损伤。抑制JNK信号通路可能是JZG预防和逆转NASH发展的潜在机制。
