Han Yu, Black Sylvester, Gong Zhengfan, Chen Zhi, Ko Jae-Kyun, Zhou Zhongshu, Xia Tianyang, Fang Dandong, Yang Donghai, Gu Daqian, Zhang Ziyue, Ren Hongmei, Duan Xudong, Reader Brenda F, Chen Ping, Li Yongsheng, Kim Jung-Lye, Li Zhongguang, Xu Xuehong, Guo Li, Zhou Xinyu, Haggard Erin, Zhu Hua, Tan Tao, Chen Ken, Ma Jianjie, Zeng Chunyu
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.
Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
J Hepatol. 2022 Mar;76(3):558-567. doi: 10.1016/j.jhep.2021.10.017. Epub 2021 Nov 1.
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.
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.
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.
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.
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.
药物性肝损伤（DILI）的治疗仍然具有挑战性，并且仍是急性肝衰竭的主要原因。MG53是一种肌肉来源的组织修复蛋白，在血液中循环，其在预防DILI中的生理作用尚未得到研究。
使用Mg53或Ripk3基因缺失的小鼠，外源性给予重组MG53蛋白（rhMG53）。采用活细胞成像、组织学、生化和分子研究方法，探讨rhMG53在肝脏保护中的细胞外和细胞内作用机制。
在小鼠中全身给予rhMG53蛋白，可以预防性和治疗性地治疗由对乙酰氨基酚、四环素、刀豆蛋白A、四氯化碳或硫代乙酰胺引起的DILI。循环中的MG53通过在质膜上与MLKL直接相互作用来保护肝细胞免受损伤。细胞外MG53可以进入肝细胞，并作为一种E3连接酶减轻RIPK3介导的MLKL磷酸化和膜易位。
我们的数据表明，MG53的膜限定信号传导和胞质双重作用在DILI期间有效地维持了肝细胞的完整性。rhMG53可能是DILI患者的一种潜在治疗选择。
治疗药物性肝损伤并阻止其进展为肝衰竭的干预措施对社会具有重要价值。本研究表明，以MG53为信使的肌肉-肝脏相互作用在保护肝细胞方面发挥着重要作用。因此,MG53是药物性肝损伤患者的一种潜在治疗选择。
