Liu Binjie, Shao Ting, Xiao Dandan, Yang Shujie, Lin Weijie, Sun Lizhu, Zhang Weiqin, Luo Meiqing, Zhao Jinlan, Yang Lei, Bai Shasha, Deng Di, Wang Caiyan, Wang Shaogui, Zhang Rong, Liu Zhongqiu, An Lin
International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China.
J Ethnopharmacol. 2025 Feb 11;341:119330. doi: 10.1016/j.jep.2025.119330. Epub 2025 Jan 6.
Cornus officinalis (CO) has been widely used as Chinese herbal medicine and has a good clinical efficacy in liver disease. In particular, it has a significant therapeutic effect on metabolic liver disease. However, systematic pharmacological studies on its hepatoprotective effect on non-alcoholic fatty liver disease (NAFLD) are lacking.
We investigated the impact of Cornus officinalis extract (COE) on two mouse models of NAFLD, screened the potential mechanisms of action by using metabolomics assays, and explored the protective effects on hepatocyte proliferation by regulating glutamate metabolism and tricarboxylic acid (TCA) cycle.
The main components of COE were identified by high performance liquid chromatograph (HPLC). Male C57BL/6J mice were subjected to construct carbon tetrachloride (CCl) or methionine choline deficient (MCD) induced NAFLD mice. Liver function and lipid biochemical indicators were detected using commercial assay kits. Masson staining, Western blot, and immunohistochemistry analyses were used for assessing hepatic injury and fibrosis. LC-MS non-targeted analysis was performed using the 1290 Ultra-High Performance Liquid Chromatograph System and the 6540 Q-TOF Mass Spectrometry. Palmitic acid (PA) induced L-02 cell model was established. The mediators in glutamate metabolism and TCA cycle were assessed by assay kits.
In vivo experiments validated that COE significantly improved liver function in NAFLD mice, reduced lipid accumulation, and alleviated pathological damage and liver fibrosis. The non-targeted metabolomics analysis combined with Ingenuity Pathway Analysis (IPA) located glutamate metabolism and the downstream TCA cycle as potential mechanisms of COE, which was further confirmed in NAFLD model mice and PA-induced L-02 cells. Finally, we confirmed that COE could promote mitochondrial energy supply by remodeling the homeostasis of the TCA cycle, thereby enhancing hepatocyte proliferation.
This study demonstrated that COE could significantly improve CCl or MCD-induced NAFLD by promoting hepatocyte proliferation. These results highlighted the potential of COE as leads for the development of innovative treatments for NAFLD.
山茱萸（CO）作为一种中草药已被广泛应用，在肝病治疗方面具有良好的临床疗效。特别是，它对代谢性肝病具有显著的治疗作用。然而，关于其对非酒精性脂肪性肝病（NAFLD）的肝保护作用的系统药理学研究尚缺乏。
我们研究了山茱萸提取物（COE）对两种NAFLD小鼠模型的影响，通过代谢组学分析筛选潜在的作用机制，并探讨其通过调节谷氨酸代谢和三羧酸（TCA）循环对肝细胞增殖的保护作用。
采用高效液相色谱仪（HPLC）鉴定COE的主要成分。雄性C57BL/6J小鼠被用于构建四氯化碳（CCl）或蛋氨酸胆碱缺乏（MCD）诱导的NAFLD小鼠模型。使用商业检测试剂盒检测肝功能和脂质生化指标。采用Masson染色、蛋白质免疫印迹法和免疫组织化学分析评估肝损伤和肝纤维化。使用1290超高效液相色谱系统和6540 Q-TOF质谱仪进行液相色谱-质谱非靶向分析。建立棕榈酸（PA）诱导的L-02细胞模型。通过检测试剂盒评估谷氨酸代谢和TCA循环中的介质。
体内实验证实，COE显著改善了NAFLD小鼠的肝功能，减少了脂质积累，减轻了病理损伤和肝纤维化。非靶向代谢组学分析结合 Ingenuity Pathway Analysis（IPA）确定谷氨酸代谢和下游TCA循环是COE的潜在作用机制，这在NAFLD模型小鼠和PA诱导的L-02细胞中得到了进一步证实。最后，我们证实COE可以通过重塑TCA循环的稳态来促进线粒体能量供应，从而增强肝细胞增殖。
本研究表明，COE可以通过促进肝细胞增殖显著改善CCl或MCD诱导的NAFLD。这些结果突出了COE作为开发NAFLD创新治疗方法的潜在先导物的潜力。
