Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis
Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis
复制标题
鼠尾草酚介导的 Sirtuin 1 激活抑制 Zeste 同源物 2 增强剂以减轻肝纤维化
DOI：
10.1016/j.phrs.2017.10.013
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发表时间：
2018-02-01
影响因子：
9.3
通讯作者：
Yao, Jihong
中科院分区：
文献类型：
--
作者：
Zhao, Huanyu;Wang, Zhecheng;Yao, Jihong
静止的肝星状细胞（HSC）活化并随后转化为肌成纤维细胞是肝纤维化发病机制的中心事件。上皮间质转化（EMT）是肝纤维化的另一个重要参与者，具有启动HSC活化的潜力，这促进了大量的肌成纤维细胞的产生。先前的研究表明，增强子Zeste同源物2（EZH 2）在肌成纤维细胞转分化中起着重要作用;然而，其潜在机制在很大程度上仍未得到解决。鼠尾草酚（CS）是从迷迭香中提取的一种化合物，具有多种药理活性。本研究旨在探讨肝纤维化中EZH 2抑制的信号转导机制和CS的抗纤维化作用。我们发现，CS显着抑制CCI 4和TGF β 1诱导的肝纤维化，并减少HSC活化和EMT。EZH 2敲低也阻止了HSC和AML-12细胞中TGF β 1诱导的这些过程。有趣的是，CS的保护作用与Sirtuin 1（SIRT 1）激活呈正相关，并伴有EZH 2抑制。SIRT 1基因敲减可减弱CS对EZH 2的抑制作用，并增加EZH 2的乙酰化程度，从而增强其稳定性。相反，在TGF β 1暴露后，SIRT 1激活显著降低了EZH 2乙酰化的水平;然而，EZH 2过表达阻止了引发肌成纤维细胞抑制的SIRT 1激活，表明EZH 2是SIRT 1的靶标。因此，SIRT 1/EZH 2调节可用作纤维化的新治疗策略。总之，该研究提供了CS激活SIRTI/EZH 2途径的证据，其抑制肌成纤维细胞产生，因此，CS可能代表抗纤维化临床治疗的有吸引力的候选者。(C)2017爱思唯尔有限公司版权所有
Quiescent hepatic stellate cell (HSC) activation and subsequent conversion into myofibroblasts is the central event in hepatic fibrosis pathogenesis. Epithelial mesenchymal transition (EMT), another vital participant in liver fibrosis, has the potential to initiate HSC activation, which promotes abundant myofibroblast production. Previous studies suggest that Enhancer of Zeste Homolog 2 (EZH2) plays a significant role in myofibroblast transdifferentiation; however, the underlying mechanisms remain largely unaddressed. Carnosol (CS), a compound extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the signaling mechanisms underlying EZH2 inhibition and the anti-fibrotic effect of CS in liver fibrosis. We found that CS significantly inhibited CCI4- and TGF beta 1-induced liver fibrosis and reduced both HSC activation and EMT. EZH2 knockdown also prevented these processes induced by TGF beta 1 in HSCs and AML-12 cells. Interestingly, the protective effect of CS was positively associated with Sirtuin 1 (SIRT1) activation and accompanied by EZH2 inhibition. SIRT1 knockdown attenuated the EZH2 inhibition induced by CS and increased EZH2 acetylation, which enhanced its stability. Conversely, upon TGF beta 1 exposure, SIRT1 activation significantly reduced the level of EZH2 acetylation; however, EZH2 overexpression prevented the SIRT1 activation that primed myofibroblast inhibition, indicating that EZH2 is a target of SIRT1. Thus, SIRT1/EZH2 regulation could be used as a new therapeutic strategy for fibrogenesis. Together, this study provides evidence of activation of the SIRTI/EZH2 pathway by CS that inhibits myofibroblast generation, and thus, CS may represent an attractive candidate for anti -fibrotic clinical therapy. (C) 2017 Elsevier Ltd. All rights reserved.