A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response

Ning Ding, Ruth T. Yu, Nanthakumar Subramaniam, Mara H. Sherman, Caroline Wilson, Renuka Rao, Mathias Leblanc, Sally Coulter, Mingxiao He, Christopher Scott, Sue L. Lau, Annette R. Atkins, Grant D. Barish, Jenny E. Gunton, Christopher Liddle, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticle

337 Scopus citations

Abstract

Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.

Original languageEnglish (US)
Pages (from-to)601-613
Number of pages13
JournalCell
Volume153
Issue number3
DOIs
StatePublished - Apr 25 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., Lau, S. L., Atkins, A. R., Barish, G. D., Gunton, J. E., Liddle, C., Downes, M., & Evans, R. M. (2013). A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell, 153(3), 601-613. https://doi.org/10.1016/j.cell.2013.03.028