Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation.
Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation.
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MLKL 缺失可通过抑制肝细胞坏死性凋亡和肝星状细胞活化来改善肝纤维化
DOI：
10.7150/thno.71400
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Xie, Xin
中科院分区：
文献类型：
--
作者：
Guo, Ren;Jia, Xiaohui;Ding, Zhenbin;Wang, Gang;Jiang, Mengmeng;Li, Bing;Chen, Shanshan;Xia, Bingqing;Zhang, Qing;Liu, Jian;Zheng, Ruting;Gao, Zhaobing;Xie, Xin
关键词：
背景：肝纤维化影响着全世界数百万人，但没有有效的治疗方法。虽然肝脏中的多种细胞类型参与纤维化过程，但肝细胞死亡被认为是触发因素。多种形式的细胞死亡，包括坏死、细胞凋亡和坏死下垂，已被报道在肝脏疾病中共存。混合谱系激酶结构域样蛋白（MLKL）是坏死性坏死途径的末端效应物。虽然坏死性上睑下垂已被报道在许多肝脏疾病中发挥重要作用，但MLKL在肝纤维化中的功能尚未被揭示。方法和结果：在这里，我们报告了MLKL水平与肝纤维化患者和动物模型中肝脏样本中的许多纤维化标志物呈正相关。小鼠Mlkl缺失可显著减轻CCl4-和胆管结扎（BDL）诱导的肝损伤和纤维化的临床症状。进一步的研究表明，Mlkl-/-通过减少肝细胞坏死和肝星状细胞（HSC）的活化来阻断肝纤维化。aav8介导的肝细胞特异性敲低Mlkl可在预防和治疗两方面显著缓解ccl4诱导的肝纤维化。结论：MLKL介导的信号通路在肝损伤和肝纤维化中起重要作用，靶向MLKL可能是治疗肝纤维化的有效途径。
Background: Liver fibrosis affects millions of people worldwide without an effective treatment. Although multiple cell types in the liver contribute to the fibrogenic process, hepatocyte death is considered to be the trigger. Multiple forms of cell death, including necrosis, apoptosis, and necroptosis, have been reported to co-exist in liver diseases. Mixed lineage kinase domain-like protein (MLKL) is the terminal effector in necroptosis pathway. Although necroptosis has been reported to play an important role in a number of liver diseases, the function of MLKL in liver fibrosis has yet to be unraveled. Methods and Results: Here we report that MLKL level is positively correlated with a number of fibrotic markers in liver samples from both patients with liver fibrosis and animal models. Mlkl deletion in mice significantly reduces clinical symptoms of CCl4- and bile duct ligation (BDL) -induced liver injury and fibrosis. Further studies indicate that Mlkl-/- blocks liver fibrosis by reducing hepatocyte necroptosis and hepatic stellate cell (HSC) activation. AAV8-mediated specific knockdown of Mlkl in hepatocytes remarkably alleviates CCl4-induced liver fibrosis in both preventative and therapeutic ways. Conclusion: Our results show that MLKL-mediated signaling plays an important role in liver damage and fibrosis, and targeting MLKL might be an effective way to treat liver fibrosis.
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影响因子：
29.4
作者：
Luedde T;Kaplowitz N;Schwabe RF
通讯作者：
Schwabe RF
影响因子：
4.7
作者：
Fabregat I;Caballero-Díaz D
通讯作者：
Caballero-Díaz D
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
16.1
作者：
Higashi T;Friedman SL;Hoshida Y
通讯作者：
Hoshida Y
DOI：
10.1038/nri3071
发表时间：
2011-10-10
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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