p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species
p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species
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p66Shc 通过调节线粒体活性氧促进肝纤维化
DOI：
10.7150/thno.29620
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Yao, Jihong
中科院分区：
文献类型：
--
作者：
Zhao, Yan;Wang, Zhecheng;Yao, Jihong
背景：p66Shc是一种介导线粒体活性氧（ROS）生成的氧化还原酶。p66Shc抑制对肝损伤具有保护作用，然而，其对肝纤维化的功能贡献尚不清楚。本研究旨在通过线粒体ROS探讨p66Shc在肝纤维化中的作用及其潜在机制。方法：p66shc沉默小鼠注射四氯化碳（CCl4）。在TGF-β1刺激前，对原代肝星状细胞（hsc）进行p66Shc沉默或过表达。结果：ccl4诱导肝纤维化小鼠p66Shc表达逐渐升高，体内p66Shc沉默可显著减弱纤维化发展，减轻肝损伤、氧化应激和HSC活化，表现为α-SMA、CTGF和TIMP1水平降低。此外，在原代造血干细胞中，p66shc介导的线粒体ROS产生在线粒体形态和细胞代谢中起着至关重要的作用。敲低p66Shc显著抑制线粒体ROS生成和nod样受体蛋白3 （NLRP3）炎性体激活，这与HSC激活密切相关，表现为α-SMA、CTGF和TIMP1水平降低。然而，p66Shc过表达会产生相反的作用，这种作用被一种特定的线粒体ROS清除剂（mito-TEMPO）抑制。更重要的是，p66Shc在肝纤维化患者中表达显著升高，并伴有NLRP3炎性体激活。结论：p66Shc通过介导线粒体ROS产生，触发NLRP3炎性体激活，是肝纤维化的关键调节因子。
Background: p66Shc is a redox enzyme that mediates mitochondrial reactive oxygen species (ROS) generation. p66Shc inhibition confers protection against liver injury, however, its functional contribution to liver fibrosis remains unclear. The aim of this study is to explore the involvement of p66Shc in liver fibrosis and underlying mechanism of p66Shc by focusing on mitochondrial ROS. Methods: p66Shc-silenced mice were injected with carbon tetrachloride (CCl4). Primary hepatic stellate cells (HSCs) were performed with p66Shc silencing or overexpression prior to TGF-β1 stimulation. Results: p66Shc expression was progressively elevated in mice with CCl4-induced liver fibrosis, and p66Shc silencing in vivo significantly attenuated fibrosis development, reducing liver damage, oxidative stress and HSC activation, indicated by the decreased α-SMA, CTGF and TIMP1 levels. Furthermore, in primary HSCs, p66Shc-mediated mitochondrial ROS production played a vital role in mitochondrial morphology and cellular metabolism. Knockdown of p66Shc significantly inhibited mitochondrial ROS production and NOD-like receptor protein 3 (NLRP3) inflammasome activation, which were closely associated with HSC activation, indicated by the decreased α-SMA, CTGF and TIMP1 levels. However, p66Shc overexpression exerted the opposite effects, which were suppressed by a specific mitochondrial ROS scavenger (mito-TEMPO). More importantly, p66Shc expression was significantly increased in human with liver fibrosis, accompanied by NLRP3 inflammasome activation. Conclusions: p66Shc is a key regulator of liver fibrosis by mediating mitochondrial ROS production, which triggers NLRP3 inflammasome activation.