衰老
肝星状细胞
转录因子
细胞生物学
生物
块(置换群论)
化学
内科学
医学
内分泌学
生物化学
数学
几何学
基因
作者
Yan Guo,Anqi Zhou,Yuanyuan Zhang,Ying Chen,Yifei Chen,Yuan Gao,Xiulian Miao
出处
期刊:Life Sciences
[Elsevier BV]
日期:2023-06-01
卷期号:328: 121824-121824
被引量:3
标识
DOI:10.1016/j.lfs.2023.121824
摘要
Aberrant liver fibrosis is a hallmark event in end-stage liver diseases. Hepatic stellate cells (HSCs) are considered the major source of myofibroblasts in the liver that produce extracellular matrix proteins to promote liver fibrosis. HSCs undergo senescence in response to various stimuli, a process that can be exploited to dampen liver fibrosis. We investigated the role of serum response factor (SRF) in this process. Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP). SRF expression was down-regulated in HSCs entering into senescence. Coincidently, SRF depletion by RNAi accelerated HSC senescence. Of note, treatment of an anti-oxidant (N-acetylcysteine or NAC) blocked HSC senescence by SRF deficiency suggesting that SRF may antagonize HSC senescence by eliminating excessive reactive oxygen species (ROS). PCR-array based screening identified peroxidasin (PXDN) as a potential target for SRF in HSCs. PXDN expression was inversely correlated with HSC senescence whereas PXDN knockdown accelerated HSC senescence. Further analysis reveals that SRF directly bound to the PXDN promoter and activated PXDN transcription. Consistently, PXDN over-expression protected whereas PXDN depletion amplified HSC senescence. Finally, PXDN knockout mice displayed diminished liver fibrosis compared to wild type mice when subjected to bile duct ligation (BDL). Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.
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