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
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
复制标题
肝细胞中前列腺六跨膜上皮抗原 3 缺陷通过抑制转化生长因子-β-激活激酶 1 保护肝脏免受缺血再灌注损伤
DOI：
10.1002/hep.30882
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发表时间：
2019-10-11
期刊：
影响因子：
13.5
通讯作者：
Zhang, Shui-Jun
中科院分区：
文献类型：
--
作者：
Guo, Wen-Zhi;Fang, Hong-Bo;Zhang, Shui-Jun
背景与目的肝缺血再灌注（I/R）损伤是影响肝移植术后发病率和死亡率的主要问题。改善肝I/R损伤后肝功能的有效策略有限。前列腺六跨膜上皮抗原3 （Steap3）是铁摄取的关键调节因子，据报道参与多种细胞类型的免疫和凋亡过程。然而，Steap3在肝I/ r诱导的肝损伤中的作用仍不清楚。方法和结果在本研究中，我们发现Steap3在肝脏I/R手术小鼠和缺氧/再氧损伤的原代肝细胞的肝组织中表达显著上调。随后，将Steap3全基因敲除（Steap3- ko）小鼠、肝细胞特异性Steap3转基因（Steap3- htg）小鼠以及相应的对照小鼠进行部分肝温I/R损伤。监测肝脏组织学、炎症反应和细胞凋亡以评估肝损伤。探讨了Steap3在体内和体外作用的分子机制。结果表明，与对照小鼠相比，Steap3-KO小鼠在肝I/R损伤后表现出肝脏损伤减轻，表现为坏死面积缩小，血清转氨酶水平降低，细胞凋亡率降低，炎症细胞浸润减少，而Steap3-HTG小鼠的表型相反。进一步的分子实验表明，Steap3缺乏可抑制肝脏I/R损伤过程中转化生长因子- β活化激酶1 （TAK1）的激活和下游c-Jun n -末端激酶（JNK）和p38信号传导。Steap3是肝脏I/R损伤的介质，通过tak1依赖性激活JNK/p38通路，调节炎症反应和细胞凋亡。以肝细胞为靶点，Steap3可能是一种很有前途的保护肝脏免受I/R损伤的方法。
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-beta-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.