Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease.
Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease.
复制标题
通过丹酚酸 B 介导的 SIRT1 上调抑制 HMGB1 释放可保护大鼠免受非酒精性脂肪肝疾病
DOI：
10.1038/srep16013
复制
发表时间：
2015-11-03
影响因子：
4.6
通讯作者：
Yao J
中科院分区：
文献类型：
--
作者：
Zeng W;Shan W;Gao L;Gao D;Hu Y;Wang G;Zhang N;Li Z;Tian X;Xu W;Peng J;Ma X;Yao J
炎症介质高迁移率族蛋白1（HMGB 1）在非酒精性脂肪性肝病（NAFLD）的发病机制中起着关键作用。然而，HMGB 1在NAFLD中的调节，特别是通过sirtuin 1（SIRT 1），仍然不清楚。在本研究中，我们研究了SIRT 1介导的HMGB 1释放抑制在NAFLD中的作用，以及从丹参中提取的水溶性酚酸B（SalB）通过SIRT 1/HMGB 1信号通路对NAFLD的影响。重要的是，SalB显着抑制HMGB 1核转位和释放，伴随SIRT 1升高。在HepG 2细胞中，棕榈酸（PA）诱导的促炎细胞因子的释放被HMGB 1小干扰RNA（siRNA）转染阻断。此外，Ex 527的药理学SIRT 1抑制诱导HMGB 1易位和释放，而白藜芦醇或SalB的SIRT 1激活逆转了这一趋势。SIRT 1 siRNA消除了SalB介导的对HMGB 1乙酰化和释放的抑制，表明SalB介导的保护作用是通过SIRT 1靶向HMGB 1去乙酰化而发生的。我们是第一个证明SIRT 1/HMGB 1通路是控制NAFLD炎症的关键治疗靶点，SalB通过SIRT 1介导的HMGB 1去乙酰化作用提供对HFD和PA诱导的肝脂肪变性和炎症的保护。
The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the regulation of HMGB1 in NAFLD, particularly through sirtuin 1 (SIRT1), remains unclear. In this study, we investigated the role of SIRT1-mediated inhibition of HMGB1 release in NAFLD and the effect of salvianolic acid B (SalB), which is a water-soluble phenolic acid extracted from RadixSalvia miltiorrhiza, on NAFLD through SIRT1/HMGB1 signaling.In vivo, SalB treatment significantly attenuated high-fat diet (HFD)-induced liver damage, hepatic steatosis and inflammation. Importantly, SalB significantly inhibited HMGB1 nuclear translocation and release, accompanied by SIRT1 elevation. In HepG2 cells, palmitic acid (PA)-induced pro-inflammatory cytokines release were blocked by HMGB1 small interfering RNA (siRNA) transfection. Moreover, pharmacological SIRT1 inhibition by Ex527 induced HMGB1 translocation and release, whereas SIRT1 activation by resveratrol or SalB reversed this trend. SIRT1 siRNA abrogated the SalB-mediated inhibition of HMGB1 acetylation and release, suggesting that SalB-mediated protection occurs by SIRT1 targeting HMGB1 for deacetylation. We are the first to demonstrate that the SIRT1/HMGB1 pathway is a key therapeutic target for controlling NAFLD inflammation and that SalB confers protection against HFD- and PA-induced hepatic steatosis and inflammation through SIRT1-mediated HMGB1 deacetylation.