肝星状细胞
HDAC4型
癌症研究
肝硬化
西妥因1
基因沉默
肝损伤
肝纤维化
生物
纤维化
组蛋白脱乙酰基酶
HDAC1型
细胞生物学
下调和上调
组蛋白
内分泌学
内科学
医学
生物化学
基因
作者
Min Li,Wenxuan Hong,Chenzhi Hao,Luyang Li,Huihui Xu,Ping Li,Yong Xu
标识
DOI:10.1016/j.bbadis.2017.09.008
摘要
Liver fibrosis is widely perceived as a host defense mechanism that aids tissue repair following liver injury. Excessive fibrogenesis, however, serves to disrupt normal liver structure and precedes such irrevocable human pathologies as cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is a hallmark event during liver fibrosis. In the present study we investigated the mechanism by which the lysine deacetylase SIRT1 regulates HSC activation. We report here that SIRT1 levels were decreased in the liver in different mouse models and in cultured HSCs undergoing activation. SIRT1 down-regulation paralleled HDAC4 up-regulation. HDAC4 was recruited to the SIRT1 promoter during HSC activation and removed acetylated histones H3 and H4 from the SIRT1 promoter leading to SIRT1 trans-repression. HDAC4 silencing restored SIRT1 expression and attenuated HSC activation in SIRT1-dependent manner. More important, selective deletion of SIRT1 in HSCs exacerbated CCl4-induced liver fibrosis in mice. Mechanistically, SIRT1 deacetylated PPARγ to block HSC activation. Together, our data reveal an HDAC4-SIRT1-PPARγ axis that contributes to the regulation of HSC activation and liver fibrosis.
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