Xiong Jingfang, Chen Gaofeng, He Ying, Zhao Changqing, Chen Dongya, Liu Yihui, Zhang Zhaolin, Wu Yijun, Xu Hong
Department of Geriatrics, Hangzhou Red Cross Hospital, Hangzhou, 310003, China.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Chem Biol Interact. 2025 Feb 1;407:111370. doi: 10.1016/j.cbi.2024.111370. Epub 2024 Dec 31.
Nonalcoholic Steatohepatitis (NASH) is a common liver disease with limited treatment options. Oxymatrine (OMT) has been reported to treat liver diseases effectively. This study aims to explore the mechanisms of OMT in NASH. Male Sprague-Dawley rats were fed a high-fat and high-sucrose diet and hepatocytes were stimulated with oleic acid (OA) to establish NASH models, then, NASH models were intervened with OMT. In vivo, liver injury and lipid accumulation extents were evaluated by serum and liver biochemical indexes, and histological analysis. In vitro, cell viability and lipid accumulation degrees were measured. Additionally, the relationships between perilipin 2 (Plin2) and liver X-activated receptor alpha (LXRα) as well as Plin2 and sterol regulatory element binding protein-1c (SREBP-1c), sirtuin 1 (Sirt1)/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway-, liver X-activated receptor (LXR)/Plin2/SREBP-1c pathway- and lipid synthesis-related proteins were detected both in vivo and in vitro. Finally, Sirt1 was knocked down in hepatocytes. OMT not only reduced serum alanine aminotransferase activity and triglyceride content, liver triglyceride and free fatty acid levels in NASH rats, but also improved hepatic injury and lipid accumulation. In vitro, OMT enhanced viability, and downregulated lipid accumulation in OA-induced hepatocytes. Both in vivo and in vitro results revealed Plin2 directly interacted with LXRα and SREBP-1c, and OMT activated Sirt1/AMPK pathway but inhibited the expressions of LXR/Plin2/SREBP-1c pathway and lipid synthesis (acetyl-CoA carboxylase, fatty acid synthase, stearoyl-Coenzyme A desaturase 1) related proteins in NASH models. Importantly, Sirt1 knockdown reversed the protective effects of OMT in OA-stimulated hepatocytes. OMT may reduce hepatic lipid synthesis in NASH by activating the Sirt1/AMPK pathway and inhibiting the LXR/Plin2/SREBP-1c pathway, suggesting that OMT may be a promising strategy for treating NASH.
非酒精性脂肪性肝炎（NASH）是一种常见的肝脏疾病，治疗选择有限。据报道，氧化苦参碱（OMT）可有效治疗肝脏疾病。本研究旨在探讨OMT治疗NASH的机制。将雄性Sprague-Dawley大鼠喂食高脂高糖饮食，并用油酸（OA）刺激肝细胞以建立NASH模型，然后用OMT对NASH模型进行干预。在体内，通过血清和肝脏生化指标以及组织学分析评估肝损伤和脂质蓄积程度。在体外，测量细胞活力和脂质蓄积程度。此外，在体内和体外检测了脂滴包被蛋白2（Plin2）与肝脏X激活受体α（LXRα）之间的关系，以及Plin2与固醇调节元件结合蛋白-1c（SREBP-1c）、沉默调节蛋白1（Sirt1）/腺苷5'-单磷酸激活蛋白激酶（AMPK）途径、肝脏X激活受体（LXR）/Plin2/SREBP-1c途径和脂质合成相关蛋白之间的关系。最后，在肝细胞中敲低Sirt1。OMT不仅降低了NASH大鼠血清丙氨酸氨基转移酶活性和甘油三酯含量、肝脏甘油三酯和游离脂肪酸水平，还改善了肝损伤和脂质蓄积。在体外，OMT增强了OA诱导的肝细胞活力，并下调了脂质蓄积。体内和体外结果均显示Plin2直接与LXRα和SREBP-1c相互作用，且OMT激活了Sirt1/AMPK途径，但在NASH模型中抑制了LXR/Plin2/SREBP-1c途径和脂质合成（乙酰辅酶A羧化酶、脂肪酸合酶、硬脂酰辅酶A去饱和酶1）相关蛋白的表达。重要的是，Sirt1敲低逆转了OMT对OA刺激的肝细胞的保护作用。OMT可能通过激活Sirt1/AMPK途径并抑制LXR/Plin2/SREBP-1c途径来减少NASH中的肝脏脂质合成，这表明OMT可能是治疗NASH的一种有前景的策略。
