Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Toxicol Lett. 2022 Feb 1;355:88-99. doi: 10.1016/j.toxlet.2021.11.014. Epub 2021 Nov 25.
Liver fibrosis is a reversible wound healing reaction characterized by abnormal accumulation of extracellular matrix (ECM) in response to liver injury. Recent studies have shown that it can be epigenetically regulated, especially by microRNAs (miRNAs). It has been acknowledged that activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Notably, our results showed that miR-195-3p was increased in HSCs isolated from CCl-treated mice and that the increase was more pronounced as the degree of liver fibrosis increased. Moreover, treatment of LX-2 cells, a human immortalized hepatic stellate cell line, with TGF-β1 resulted remarkable upregulation of miR-195-3p. Gain-of-function and loss-of-function experiments have suggested that the increased levels of miR-195-3p inhibit the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR signaling pathway in liver fibrosis, thereby contributing to HSC activation and proliferation and promoting the expression of profibrotic genes, such as α-SMA and collagen I, in LX-2 cells, which accelerates the accumulation of fibrous extracellular matrix deposition in the liver, while knockdown of miR-195-3p induced the opposite effect. Taken together, these results provide evidence for the harmful role of miR-195-3p in CCl-treated mouse liver fibrosis.
肝纤维化是一种可逆转的创伤愈合反应，其特征是在外伤后肝脏损伤时细胞外基质（ECM）的异常积累。最近的研究表明，它可以被表观遗传调控，特别是通过 microRNAs（miRNAs）。已经认识到肝星状细胞（HSCs）的激活是肝纤维化起始和进展的关键步骤。值得注意的是，我们的研究结果表明，miR-195-3p 在 CCl 处理的小鼠分离的 HSCs 中增加，并且随着肝纤维化程度的增加而增加得更为明显。此外，用 TGF-β1 处理人永生化肝星状细胞系 LX-2 细胞可显著上调 miR-195-3p。功能获得和功能丧失实验表明，miR-195-3p 水平的升高抑制了磷酸酶和张力同源物缺失于染色体 10（PTEN）的表达，PTEN 是肝纤维化中 PI3K/Akt/mTOR 信号通路的负调节剂，从而促进 HSC 的激活和增殖，并促进纤维化基因如α-SMA 和胶原蛋白 I 在 LX-2 细胞中的表达，从而加速肝脏中纤维细胞外基质的积累，而 miR-195-3p 的敲低则诱导相反的效果。综上所述，这些结果为 miR-195-3p 在 CCl 处理的小鼠肝纤维化中的有害作用提供了证据。
