Wang Jingjie, Zhang Yitong, Ma Yanyun, Zhao Suhan, Wang Jiucun, Chen Hongtan, Zhang Jun, Liu Jie
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
J Gastroenterol Hepatol. 2024 Jul;39(7):1403-1412. doi: 10.1111/jgh.16443. Epub 2024 Feb 18.
Hepatic stellate cells (HSCs) are critical regulator contributing to the onset and progression of liver fibrosis. Chronic liver injury triggers HSCs to undergo vast changes and trans-differentiation into a myofibroblast HSCs, the mechanism remains to be elucidated. This study investigated that the involvement of hydroxymethylase TET1 (ten-eleven translocation 1) in HSC activation and liver fibrosis. It is revealed that TET1 levels were downregulated in the livers in mouse models of liver fibrosis and patients with cirrhosis, as well as activated HSCs in comparison to quiescent HSCs. In vitro data showed that the inhibition of TET1 promoted the activation HSC, whereas TET1 overexpression inhibited HSC activation. Moreover, TET1 could regulate KLF2 (Kruppel-like transcription factors) transcription by promoting hydroxymethylation of its promoter, which in turn suppressed the activation of HSCs. In vivo, it is confirmed that liver fibrosis was aggravated in Tet1 knockout mice after CCl4 injection, accompanied by excessive activation of primary stellate cells, in contrast to wild-type mice. In conclusion, we suggested that TET1 plays a significant role in HSC activation and liver fibrosis, which provides a promising target for anti-fibrotic therapies.
肝星状细胞（HSCs）是导致肝纤维化发生和发展的关键调节因子。慢性肝损伤促使肝星状细胞发生巨大变化并转分化为肌成纤维细胞样肝星状细胞，其机制仍有待阐明。本研究探讨了羟甲基化酶TET1（10-11易位蛋白1）在肝星状细胞激活和肝纤维化中的作用。研究发现，在肝纤维化小鼠模型和肝硬化患者的肝脏中，以及与静止肝星状细胞相比的活化肝星状细胞中，TET1水平下调。体外实验数据表明，抑制TET1可促进肝星状细胞活化，而TET1过表达则抑制肝星状细胞活化。此外，TET1可通过促进KLF2（Kruppel样转录因子）启动子的羟甲基化来调节其转录，进而抑制肝星状细胞的活化。在体内，与野生型小鼠相比，四氯化碳注射后Tet1基因敲除小鼠的肝纤维化加重，伴有原代星状细胞的过度活化。总之，我们认为TET1在肝星状细胞活化和肝纤维化中起重要作用，这为抗纤维化治疗提供了一个有前景的靶点。
