RIP1 kinase inactivation protects against acetaminophen-induced acute liver injury in mice

Yuguo Yi; Weigao Zhang; Liang Tao; Qianchao Shao; Qian Xu; Yuxin Chen; Haibing Zhang; Jianfa Zhang; Dan Weng

doi:10.1016/j.freeradbiomed.2021.07.034

RIP1 kinase inactivation protects against acetaminophen-induced acute liver injury in mice

Free Radic Biol Med. 2021 Oct:174:57-65. doi: 10.1016/j.freeradbiomed.2021.07.034. Epub 2021 Jul 26.

Authors

Yuguo Yi¹, Weigao Zhang¹, Liang Tao¹, Qianchao Shao¹, Qian Xu¹, Yuxin Chen², Haibing Zhang³, Jianfa Zhang¹, Dan Weng⁴

Affiliations

¹ Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
² Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, 210008, China.
³ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 100864, China.
⁴ Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. Electronic address: danweng@njust.edu.cn.

PMID: 34324981
DOI: 10.1016/j.freeradbiomed.2021.07.034

Abstract

Many studies have investigated the role of receptor-interacting protein 1 (RIP1) kinase in acetaminophen (APAP) overdose-induced acute liver injury. However, the results were not consistent and there still remain controversies. Importantly, in these previous studies, the usage of DMSO to dissolve the RIP1 kinase inhibitor Nec-1, resulted in misleading conclusion. Our study aimed to determine the role of RIP1 kinase in APAP-induced liver injury, via genetically or pharmaceutically inhibition of RIP1 kinase activity. Our results indicated that APAP-induced liver injury was significantly attenuated in RIP1 kinase-dead (Rip1^K45A/K45A) mice compared to WT control. High dosage of APAP-induced mortality was also rescued by RIP1 kinase inactivation. In agreement, RIP1 kinase inhibitor, Nec-1 which was formulated with PEG400, could efficiently alleviate APAP-induced hepatotoxicity. For the underlying mechanism, our results suggested that RIP1 kinase inactivation did not influence the hepatic GSH depletion, but significantly reduced the hepatic cell death and inflammation induced by APAP treatment. Using bone marrow transplantation model, we also demonstrated that it was RIP1 kinase activity in tissue-resident hepatic cells other than hematopoietic-derived cells mainly responsible for APAP-induced liver injury. Our study confirmed the important role of RIP1 kinase activity in APAP-induced acute liver failure.

Keywords: Acetaminophen; Cell death; Hepatotoxicity; Inflammation; RIP1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetaminophen / toxicity
Animals
Chemical and Drug Induced Liver Injury* / genetics
Chemical and Drug Induced Liver Injury* / prevention & control
Hepatocytes
Liver
Liver Failure, Acute*
Mice
Mice, Inbred C57BL

Substances

Acetaminophen