SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice
SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice
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SIRT1 通过阻断小鼠肝星状细胞活化来拮抗肝纤维化
DOI：
10.1096/fj.201700612r
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发表时间：
2018-01-01
期刊：
影响因子：
4.8
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Li, Min;Hong, Wenxuan;Xu, Yong
肝星状细胞（HSC）是肝纤维化的主要来源，有助于肝硬化。当被激活时，HSC转分化成肌成纤维细胞并经历深刻的功能改变，同时进行转录组的彻底检查，其机制在很大程度上仍不清楚。我们研究了III类去乙酰化酶sirtuin [沉默信息调节因子1（SIRT 1）]在HSC活化和肝纤维化中的作用。SIRT 1水平在肝纤维化小鼠模型、肝硬化患者和活化的HSC中（与静止的HSC相反）的肝脏中下调。SIRT 1激活停止，而SIRT 1抑制促进HSC转分化为肌成纤维细胞。与野生型同窝小鼠相比，HSC特异性SIRT 1缺失[条件性敲除（cKO）]、接受CCl 4（1 mg/kg）注射或胆管结扎的小鼠肝纤维化加重。SIRT 1通过去乙酰化zeste增强子同源物2（EZH 2）调节静止HSC中过氧化物酶体增殖物激活受体Y（PPARg）的转录。最后，EZH 2抑制或PPARg活化改善cKO小鼠中的纤维化。总之，我们的数据表明SIRT 1在指导HSC表型转变中起着重要作用。Li，M.，洪伟，郝，C.，Li，L.，吴，D.，Shen，A.，卢，J，郑宇，Li，P.，Xu，Y. SIRT 1通过阻断小鼠肝星状细胞活化拮抗肝纤维化FASEB J. 32，500 - 511（2018）。www.fasebj.org
Hepatic stellate cells (HSCs) are a maj or source of fibrogenesis in the liver, contributing to cirrhosis. When activated, HSCs transdifferentiate into myofibroblasts and undergo profound functional alterations paralleling an overhaul of the transcriptome, the mechanism of which remains largely undefined. We investigated the involvement of the class III deacetylase sirtuin [silent information regulator 1 (SIRT1)] in HSC activation and liver fibrosis. SIRT1 levels were down‐regulated in the livers in mouse models of liver fibrosis, in patients with cirrhosis, and in activated HSCs as opposed to quiescent HSCs. SIRT1 activation halted, whereas SIRT1 inhibition promoted, HSC transdifferentiation into myofibroblasts. Liver fibrosis was exacerbated in mice with HSC‐specific deletion of SIRT1 [conditional knockout (cKO)], receiving CCl4 (1 mg/kg) injection or subjected to bile duct ligation, compared to wild‐type littermates. SIRT1 regulated peroxisome proliferator activated receptor Y (PPARg) transcription by deacetylating enhancer of zeste homolog 2 (EZH2) in quiescent HSCs. Finally, EZH2 inhibition or PPARg activation ameliorated fibrogenesis in cKO mice. In summary, our data suggest that SIRT1 plays an essential role guiding the transition of HSC phenotypes.—Li, M., Hong, W., Hao, C., Li, L., Wu, D., Shen, A., Lu, J., Zheng, Y., Li, P., Xu, Y. SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice. FASEB J. 32, 500‐511 (2018). www.fasebj.org