Wu Yuting, Liu Xuejiao, Zhou Qun, Huang Cheng, Meng Xiaoming, Xu Fengyun, Li Jun
School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
Toxicol Appl Pharmacol. 2015 Dec 1;289(2):163-76. doi: 10.1016/j.taap.2015.09.028. Epub 2015 Oct 3.
SIRT1 (silent information regulator 1), a conserved NAD+-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis.
沉默信息调节因子1（SIRT1）是一种保守的依赖烟酰胺腺嘌呤二核苷酸（NAD+）的组蛋白脱乙酰酶，与多种生物学过程密切相关。此外，SIRT1在酒精性肝病、非酒精性脂肪性肝病和肝癌中的重要作用已被广泛报道。最近，SIRT1在器官纤维化疾病中发现了新作用。在此，我们研究了SIRT1对肝纤维化的抑制作用。在四氯化碳处理的小鼠肝脏中，SIRT1蛋白显著减少。用转化生长因子-β1（TGF-β1）刺激肝星状细胞系LX-2细胞也导致SIRT1蛋白显著抑制。然而，SIRT1质粒可抑制TGF-β1诱导的LX-2细胞活化，同时伴有细胞凋亡相关蛋白上调。SIRT1过表达也减弱了TGF-β1诱导的肌成纤维细胞标志物α-平滑肌肌动蛋白（α-SMA）和I型胶原α1（COL1a）的表达。然而，肝纤维化恢复的重要特征不仅是活化星状细胞的凋亡，还包括肌成纤维细胞样表型向静止样表型的逆转。在体内自发性肝纤维化逆转模型和体外异丁基甲基黄嘌呤、地塞米松和胰岛素（MDI）诱导的逆转星状细胞中观察到SIRT1蛋白恢复，强制表达SIRT1也促进活化星状细胞的逆转。此外，长链非编码RNA转移相关肺腺癌转录本1（lncRNA MALAT1）在肝纤维化中表达增加。RNA干扰介导的MALAT1抑制导致肌成纤维细胞标志物减少和SIRT1蛋白恢复。这些观察结果表明，SIRT1促进活化LX-2细胞的凋亡和逆转，且在肝纤维化中SIRT1可能受MALAT1调控。因此，SIRT1可被视为肝纤维化转化研究中有价值的治疗靶点。
