Yu Han1, Sylvester Black2, Zhengfan Gong1, Zhi Chen1, Jae-Kyun Ko2, Zhongshu Zhou1, Tianyang Xia1, Dandong Fang1, Donghai Yang1, Daqian Gu1, Ziyue Zhang1, Hongmei Ren1, Xudong Duan3, Brenda F Reader2, Ping Chen4, Yongsheng Li5, Jung-Lye Kim2, Zhongguang Li6, Xuehong Xu7, Li Guo5, Xinyu Zhou2, Erin Haggard2, Hua Zhu2, Tao Tan2, Ken Chen8, Jianjie Ma9, Chunyu Zeng10. 1. Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China. 2. Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA. 3. Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China. 4. Department of Hepatobiliary Surgery, Daping Hospital, Third Military Medical University, Chongqing, China. 5. Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China. 6. Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China. 7. Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China. 8. Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China. Electronic address: ck_tmmu@sina.com. 9. Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA. Electronic address: Jianjie.Ma@osumc.edu. 10. Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China. Electronic address: chunyuzeng01@163.com.
Abstract
BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.
BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.