Serum response factor activates peroxidasin transcription to block senescence of hepatic stellate cells
Life sciences(2023)
摘要
Aims: 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.Methods and materials: Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP).Results: 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 acti-vated 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).Significance: Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.
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关键词
Liver fibrosis,Hepatic stellate cell,Senescence,ROS
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