Serum response factor (SRF) promotes ROS generation and hepatic stellate cell activation by epigenetically stimulating NCF1/2 transcription

Ming Kong, Xuyang Chen, Fangqiao Lv, Haozhen Ren, Zhiwen Fan, Hao Qin, Liming Yu, Xiaolei Shi, Yong Xu

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Activation of hepatic stellate cells (HSC) is a hallmark event in liver fibrosis. Accumulation of reactive oxygen species (ROS) serves as a driving force for HSC activation. The regulatory subunits of the NOX complex, NCF1 (p47phox) and NCF2 (p67phox), are up-regulated during HSC activation contributing to ROS production and liver fibrosis. The transcriptional mechanism underlying NCF1/2 up-regulation is not clear. In the present study we investigated the role of serum response factor (SRF) in HSC activation focusing on the transcriptional regulation of NCF1/2. We report that compared to wild type littermates HSC-conditional SRF knockout (CKO) mice exhibited a mortified phenotype of liver fibrosis induced by thioacetamide (TAA) injection or feeding with a methionine-and-choline deficient diet (MCD). More importantly, SRF deletion attenuated ROS levels in HSCs in vivo. Similarly, SRF knockdown in cultured HSCs suppressed ROS production in vitro. Further analysis revealed that SRF deficiency resulted in repression of NCF1/NCF2 expression. Mechanistically, SRF regulated epigenetic transcriptional activation of NCF1/NCF2 by interacting with and recruiting the histone acetyltransferase KAT8 during HSC activation. In conclusion, we propose that SRF integrates transcriptional activation of NCF1/NCF2 and ROS production to promote liver fibrosis.

Original languageEnglish (US)
Article number101302
JournalRedox Biology
Volume26
DOIs
StatePublished - Sep 2019
Externally publishedYes

Keywords

  • Hepatic stellate cell
  • Liver fibrosis
  • Neutrophil cytosolic factor
  • Reactive oxygen species
  • Serum response factor
  • Transcriptional regulation

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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