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

Abstract

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.

• Authors: Ren Guo, Xiaohui Jia, Zhenbin Ding, Gang Wang, Mengmeng Jiang, Bing Li, Shanshan Chen, Bingqing Xia, Qing Zhang, Jian Liu, Ruting Zheng, Zhaobing Gao, Xin Xie
• Journal: Theranostics (Theranostics) Vol. 12 Issue 11 Pg. 5220-5236 ( 2022) ISSN: 1838-7640 [Electronic] Australia
• PMID: 35836819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• MLKL protein, human
• MLKL protein, mouse
• Protein Kinases

Topics

• Animals
• Apoptosis
• Fibrosis
• Hepatic Stellate Cells (metabolism)
• Hepatocytes (metabolism)
• Humans
• Liver Cirrhosis (metabolism)
• Mice
• Necroptosis
• Necrosis (metabolism)
• Protein Kinases (genetics, metabolism)