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

Ning Ding, Ruth T. Yu, Nanthakumar Subramaniam, Mara 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

309 Citations (Scopus)

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
Externally publishedYes

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Calcitriol Receptors
Networks (circuits)
Liver
Hepatic Stellate Cells
Liver Cirrhosis
Genes
Ligands
Wound Healing
Fibrosis
Chemical activation
Chromatin Assembly and Disassembly
Knockout Mice
Chromatin
Extracellular Matrix
Binding Sites
Genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ding, N., Yu, R. T., Subramaniam, N., Sherman, M., Wilson, C., Rao, R., ... 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

A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. / Ding, Ning; Yu, Ruth T.; Subramaniam, Nanthakumar; Sherman, Mara; Wilson, Caroline; Rao, Renuka; Leblanc, Mathias; Coulter, Sally; He, Mingxiao; Scott, Christopher; Lau, Sue L.; Atkins, Annette R.; Barish, Grant D.; Gunton, Jenny E.; Liddle, Christopher; Downes, Michael; Evans, Ronald M.

In: Cell, Vol. 153, No. 3, 25.04.2013, p. 601-613.

Research output: Contribution to journalArticle

Ding, N, Yu, RT, Subramaniam, N, Sherman, M, Wilson, C, Rao, R, Leblanc, M, Coulter, S, He, M, Scott, C, Lau, SL, Atkins, AR, Barish, GD, Gunton, JE, Liddle, C, Downes, M & Evans, RM 2013, 'A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response', Cell, vol. 153, no. 3, pp. 601-613. https://doi.org/10.1016/j.cell.2013.03.028
Ding, Ning ; Yu, Ruth T. ; Subramaniam, Nanthakumar ; Sherman, Mara ; Wilson, Caroline ; Rao, Renuka ; Leblanc, Mathias ; Coulter, Sally ; He, Mingxiao ; Scott, Christopher ; Lau, Sue L. ; Atkins, Annette R. ; Barish, Grant D. ; Gunton, Jenny E. ; Liddle, Christopher ; Downes, Michael ; Evans, Ronald M. / A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. In: Cell. 2013 ; Vol. 153, No. 3. pp. 601-613.
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