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Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1
Author(s) -
Guo WenZhi,
Fang HongBo,
Cao ShengLi,
Chen SanYang,
Li Jie,
Shi JiHua,
Tang HongWei,
Zhang Yi,
Wen PeiHao,
Zhang JiaKai,
Wang ZhiHui,
Shi XiaoYi,
Pang Chun,
Yang Han,
Hu BoWen,
Zhang ShuiJun
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30882
Subject(s) - liver injury , liver transplantation , reperfusion injury , apoptosis , endocrinology , in vivo , transplantation , ischemia , biology , medicine , immunology , pathology , cancer research , biochemistry , microbiology and biotechnology
Background and Aims Hepatic ischemia‐reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six‐transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R‐induced liver damage remains largely unclear. Approach and Results In the present study, we found that Steap3 expression was significantly up‐regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout ( Steap3‐ KO) mice, hepatocyte‐specific Steap3 transgenic ( Steap3‐ HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro . The results demonstrated that, compared with control mice, Steap3‐ KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3‐ HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor‐β–activated kinase 1 (TAK1) activation and downstream c‐Jun N‐terminal kinase (JNK) and p38 signaling during hepatic I/R injury. Conclusions Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1‐dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.