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Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation

文献类型：期刊论文

作者Guo, Ren9; Jia, Xiaohui8,9; Ding, Zhenbin5,6,7; Wang, Gang4; Jiang, Mengmeng3; Li, Bing2,8,9; Chen, Shanshan8,9; Xia, Bingqing9; Zhang, Qing2,9; Liu, Jian9
刊名THERANOSTICS
出版日期2022
卷号12期号:11页码:5220-5236
ISSN号1838-7640
关键词Mixed lineage kinase domain-like protein MLKL liver fibrosis liver parenchymal cells hepatocyte hepatic stellate cells necroptosis
DOI10.7150/thno.71400
通讯作者Xie, Xin(xxie@simm.ac.cn)
英文摘要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.
WOS关键词MIXED LINEAGE KINASE ; NLRP3 INFLAMMASOME ; TGF-BETA ; REGRESSION ; MACROPHAGES ; MECHANISMS ; CIRRHOSIS ; PROTECTS
资助项目Chinese Academy of Sciences[XDA16010202] ; Chinese Academy of Sciences[XDA16021308] ; National Natural Science Foundation of China[32000504] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[81972229] ; National Natural Science Foundation of China[82172610] ; Ministry of Science and Technology of China[2017YFA0104002] ; China Postdoctoral Science Foundation[2018M642117]
WOS研究方向Research & Experimental Medicine
语种英语
出版者IVYSPRING INT PUBL
WOS记录号WOS:000830834100011
源URL[http://119.78.100.183/handle/2S10ELR8/302013]  
专题新药研究国家重点实验室
通讯作者Xie, Xin
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201203, Peoples R China
5.Fudan Univ, Shanghai Xuhui Cent Hosp, Zhongshan Xuhui Hosp, Shanghai 200031, Peoples R China
6.Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai 200031, Peoples R China
7.Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Dept Liver Surg & Transplantat, Shanghai 200031, Peoples R China
8.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
9.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Ren,Jia, Xiaohui,Ding, Zhenbin,et al. Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation[J]. THERANOSTICS,2022,12(11):5220-5236.
APA Guo, Ren.,Jia, Xiaohui.,Ding, Zhenbin.,Wang, Gang.,Jiang, Mengmeng.,...&Xie, Xin.(2022).Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation.THERANOSTICS,12(11),5220-5236.
MLA Guo, Ren,et al."Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation".THERANOSTICS 12.11(2022):5220-5236.

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来源：上海药物研究所

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