Eupatilin Ameliorates Hepatic Fibrosis and Hepatic Stellate Cell Activation by Suppressing β-catenin/PAI-1 Pathway.
Eupatilin Ameliorates Hepatic Fibrosis and Hepatic Stellate Cell Activation by Suppressing β-catenin/PAI-1 Pathway.
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尤帕替林通过抑制β-catenin/PAI-1通路改善肝纤维化和肝星状细胞活化。
DOI：
10.3390/ijms24065933
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发表时间：
2023-03-21
影响因子：
5.6
通讯作者：
Chen, Zhiwei
中科院分区：
文献类型：
--
作者：
Hu, Jinyuan;Liu, Yuanyuan;Pan, Zheng;Huang, Xuekuan;Wang, Jianwei;Cao, Wenfu;Chen, Zhiwei
肝星状细胞(HSCs)的激活在肝纤维化中起关键作用。因此，抑制HSC的激活是一种有效的抗纤维化策略。虽然已有研究表明，艾蒿中发现的生物活性黄酮类化合物eupatilin具有抗肝纤维化的特性，但目前eupatilin对肝纤维化的作用尚不清楚。在本研究中，我们使用了人肝星状细胞系LX-2和经典的CCl4诱导的小鼠肝纤维化模型进行了体外和体内实验。我们发现Eupatilin显著抑制LX-2细胞中纤维化标志物COL1、α1和α-SMA以及其他胶原蛋白的水平。同时，Eupatilin显著抑制LX-2细胞的增殖，表现为细胞存活率降低，c-Myc、cyClinB1、Cyclin D1和CDK6表达下调。此外，Eupatilin以剂量依赖的方式降低PAI-1的水平，并且使用PAI-1特异性shRNA抑制PAI-1的表达显著抑制LX-2细胞中COL1α1、α-SMA和上皮-间充质转化标记N-钙粘素的水平。Western blotting结果显示，Eupatilin可降低LX-2细胞β-连环蛋白的蛋白水平及其核转位，而对β-连环蛋白的转录水平无明显影响。此外，对肝脏的组织病理学变化以及肝功能和纤维化指标的分析表明，Eupatilin显著减轻了CCl4处理的小鼠的肝纤维化。综上所述，Eupatilin通过抑制β-连环蛋白/纤溶酶原激活物-1途径来改善肝纤维化和肝星状细胞活化。
The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found in Artemisia argyi, has anti-fibrotic properties, the effect of eupatilin on hepatic fibrosis is currently unclear. In this study, we used the human hepatic stellate cell line LX-2 and the classical CCl4-induced hepatic fibrosis mouse model for in vitro and vivo experiments. We found that eupatilin significantly repressed the levels of the fibrotic markers COL1α1 and α-SMA, as well as other collagens in LX-2 cells. Meanwhile, eupatilin markedly inhibited LX-2 cell proliferation, as verified by the reduced cell viability and down-regulation of c-Myc, cyclinB1, cyclinD1, and CDK6. Additionally, eupatilin decreased the level of PAI-1 in a dose-dependent manner, and knockdown of PAI-1 using PAI-1-specific shRNA significantly suppressed the levels of COL1α1, α-SMA, and the epithelial–mesenchymal transition (EMT) marker N-cadherin in LX-2 cells. Western blotting indicated that eupatilin reduced the protein level of β-catenin and its nuclear translocation, while the transcript level of β-catenin was not affected in LX-2 cells. Furthermore, analysis of histopathological changes in the liver and markers of liver function and fibrosis revealed that hepatic fibrosis in CCl4-treated mice was markedly alleviated by eupatilin. In conclusion, eupatilin ameliorates hepatic fibrosis and hepatic stellate cell activation by suppressing the β-catenin/PAI-1 pathway.
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