Lin Guo-Shuai, Zhao Mao-Mao, Fu Qi-Chao, Zhao Shu-Yi, Ba Tao-Tao, Yu Hong-Xia
Department of Infectious Disease, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
Department of Gastroenterology, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
Drug Dev Res. 2022 Nov;83(7):1613-1622. doi: 10.1002/ddr.21981. Epub 2022 Aug 17.
Alcoholic liver disease is one of the diseases with the highest fatality rate worldwide. The cellular process of autophagy which recycles damaged organelles to maintain protein and organelle homeostasis is found to positively influence survival during hepatic insufficiency, although the mechanism is poorly understood. Palmatine (PLT) has a variety of biological functions, such as broad-spectrum antibacterial action, neuroprotective, antioxidant stress, and antiviral and anti-inflammatory activities. However, it is not known whether PLT has a protective effect against alcoholic liver injury. Here, we investigated the protective effect of PLT in a cellular model of alcohol-induced acute liver injury and further explored its mechanism of action. In this study, we show for the first time that PLT attenuates alcohol-induced hepatocyte injury by promoting autophagy to play an essential protective role. As PLT treatment induced a brief increase in LC3-II conversion and p62 degradation, it also upregulated the expression of ATG5 and ATG7. The expression levels of the proapoptotic proteins Bax, Caspase 3, and Caspase 9 significantly decreased, while the antiapoptotic protein levels of Bcl-2 upregulated after treatment with PLT. However, in presence of the autophagy inhibitor, 3-methyladenine, the effect of PLT in inhibiting ethanol-induced hepatocyte injury reversed significantly. Mechanistically, the protective effects of PLT may be mediated by promoting the activation of the AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. Therefore, we believe that the development of alcoholic liver injuries may be controlled by PLT by inhibiting hepatocyte apoptosis through the autophagy pathway. The study lays a solid theoretical and practical basis for future animal models and clinical studies of PLT.
酒精性肝病是全球死亡率最高的疾病之一。自噬是一种细胞过程，可回收受损细胞器以维持蛋白质和细胞器的稳态，尽管其机制尚不清楚，但已发现自噬对肝功能不全时的生存有积极影响。巴马汀（PLT）具有多种生物学功能，如广谱抗菌作用、神经保护、抗氧化应激以及抗病毒和抗炎活性。然而，尚不清楚PLT是否对酒精性肝损伤具有保护作用。在此，我们研究了PLT在酒精诱导的急性肝损伤细胞模型中的保护作用，并进一步探讨了其作用机制。在本研究中，我们首次表明PLT通过促进自噬减轻酒精诱导的肝细胞损伤，发挥重要的保护作用。由于PLT处理导致LC3-II转化率短暂增加和p62降解，它还上调了ATG5和ATG7的表达。促凋亡蛋白Bax、Caspase 3和Caspase 9的表达水平显著降低，而PLT处理后抗凋亡蛋白Bcl-2的水平上调。然而，在自噬抑制剂3-甲基腺嘌呤存在的情况下，PLT抑制乙醇诱导的肝细胞损伤的作用显著逆转。从机制上讲，PLT的保护作用可能是通过促进AMP激活的蛋白激酶/雷帕霉素哺乳动物靶标信号通路的激活来介导的。因此，我们认为酒精性肝损伤的发展可能通过PLT通过自噬途径抑制肝细胞凋亡来控制。该研究为PLT未来的动物模型和临床研究奠定了坚实的理论和实践基础。
