Mkp-1 protects mice against toxin-induced liver damage by promoting the Nrf2 cytoprotective response
Mkp-1 protects mice against toxin-induced liver damage by promoting the Nrf2 cytoprotective response
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Mkp-1 通过促进 Nrf2 细胞保护反应来保护小鼠免受毒素引起的肝损伤
DOI：
10.1016/j.freeradbiomed.2017.12.010
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发表时间：
2018-02-01
影响因子：
7.4
通讯作者：
Tang, Xiuwen
中科院分区：
文献类型：
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作者：
Luo, Lin;Chen, Yeru;Tang, Xiuwen
本研究旨在探讨丝裂原激活蛋白激酶磷酸酶 1 (Mkp-1) 对毒素引起的肝损伤的可能保护作用。在这里，我们发现了 Mkp-1（一种双苏氨酸/酪氨酸磷酸酶）和核因子红细胞 2 相关因子 2 (Nrf2)（肝脏防御系统的关键调节因子）之间的正反馈回路。 Mkp-1(-/-) 小鼠表现出 Nrf2、II 期基因产物和肝脏中谷胱甘肽 (GSH) 还原蛋白水平的降低。 Nrf2 激活剂丁基羟基苯甲醚 (BHA) 或萝卜硫素对解毒酶的诱导作用在 Mkp-1(-/-) 小鼠的肝脏和小肠中减弱，表明 Nrf2 信号通路因 Mkp-1 缺陷而受损。 Mkp-1(-/-) 小鼠在一次接触肝毒素四氯化碳 (CCl4) 后，比野生型 (WT) 小鼠遭受更严重的肝损伤。 BHA 部分挽救了 WT 小鼠中 CCl4 诱导的肝损伤，但不能挽救 Mkp-1(-/-) 小鼠的肝损伤，这表明 Mkp-1 需要激活 Nrf2 信号传导来对抗肝损伤。从机制上讲，Mkp-1通过与转录因子中的Neh2结构域直接相互作用上调Nrf2，而Nrf2通过与Mkp-1启动子中-1719至-1710 bp的ARE位点结合来增强Mkp-1 mRNA的表达。我们的结果揭示了 Mkp-1 在维持肝脏氧化还原稳态中的新作用。因此，旨在增强 Mkp-1 表达的策略可能有益于保护肝脏，并可能为毒素引起的肝损伤提供新的治疗方法。
The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1(-/-) mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1(-/-) mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency. Mkp-1(-/-) mice suffered more severe liver injury after a single exposure to hepatotoxin carbon tetrachloride (CCl4) than their wild-type (WT) counterparts. BHA partially rescued the CCl4-induced liver damage in WT mice, but not in Mkp-1(-/-) mice, suggesting the requirement of Mkp-1 in the activation of Nrf2 signaling against the liver injury. Mechanistically, Mkp-1 upregulated Nrf2 through a direct interaction with the Neh2 domain in the transcription factor, while Nrf2 enhanced the expression of Mkp-1 mRNA by binding to the ARE site at -1719 to -1710 bp in the Mkp-1 promoter. Our results reveal novel role of Mkp-1 in the maintenance of redox homeostasis in the liver. Thus, strategies aimed at augmenting Mkp-1 expression may be beneficial in protecting the liver and may provide novel therapeutic approaches to toxin-induced liver injury.