SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model.
SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model.
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SRT1720 可减轻小鼠模型中 ANIT 诱导的胆汁淤积
DOI：
10.3389/fphar.2017.00256
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发表时间：
2017
影响因子：
5.6
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Yu L;Liu X;Yuan Z;Li X;Yang H;Yuan Z;Sun L;Zhang L;Jiang Z
肝内胆汁淤积症（Intrahepatic Cholestasis，ICP）是胆汁酸在肝内及全身蓄积引起的一种沿着肝毒性的临床综合征。胆汁淤积症的发病机制有几个关键因素，如炎症、胆汁酸转运蛋白的失调和氧化应激。SIRT 1被认为是III类组蛋白脱乙酰酶（HDAC）。一系列研究表明，SIRT 1是调节肝脏胆汁酸代谢的重要因子之一。SRT 1720是一种SIRT 1激活剂，其活性是白藜芦醇的1000倍，本文旨在研究SRT 1720对α-萘异硫氰酸酯（ANIT）所致小鼠肝毒性和胆汁淤积的保护作用。结果显示，SRT 1720处理增加了FXR和Nrf 2基因表达，以防止ANIT诱导的肝毒性和胆汁淤积。肝胆汁酸转运蛋白的mRNA水平也被SRT 1720改变。此外，SRT 1720通过增加Nrf 2、SOD、GCLc、GCLm、Nqo 1和HO-1基因表达来增强抗氧化系统。总之，SRT 1720可以提供保护作用以治愈ANIT诱导的肝毒性和胆汁淤积，这部分是通过FXR和Nrf 2激活实现的。提示SIRT 1可作为治疗胆汁淤积症的一个靶点。
Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice. The findings revealed that SRT1720 treatment increased FXR and Nrf2 gene expressions to shield against hepatotoxicity and cholestasis induced by ANIT. The mRNA levels of hepatic bile acid transporters were also altered by SRT1720. Furthermore, SRT1720 enhanced the antioxidative system by increasing Nrf2, SOD, GCLc, GCLm, Nqo1, and HO-1 gene expressions. In conclusion, a protective influence could be provided by SRT1720 to cure ANIT-induced hepatotoxicity and cholestasis, which was partly through FXR and Nrf2 activations. These results indicated that SIRT1 could be regarded as a therapeutic target to cure the cholestasis.