BRD4 is a novel therapeutic target for liver fibrosis

Ning Ding, Nasun Hah, Ruth T. Yu, Mara H. Sherman, Chris Benner, Mathias Leblanc, Mingxiao He, Christopher Liddle, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4(BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

Original languageEnglish (US)
Pages (from-to)15713-15718
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number51
DOIs
StatePublished - Dec 22 2015

Keywords

  • Antifibrotic therapy
  • BET inhibitor
  • BRD4
  • Hepatic stellate cell
  • Liver fibrosis

ASJC Scopus subject areas

  • General

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    Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., & Evans, R. M. (2015). BRD4 is a novel therapeutic target for liver fibrosis. Proceedings of the National Academy of Sciences of the United States of America, 112(51), 15713-15718. https://doi.org/10.1073/pnas.1522163112