RGD Reference Report - A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. - Rat Genome Database

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

Authors: Ding, Ning  Yu, Ruth T  Subramaniam, Nanthakumar  Sherman, Mara H  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 
Citation: Ding N, etal., Cell. 2013 Apr 25;153(3):601-13. doi: 10.1016/j.cell.2013.03.028.
RGD ID: 14402027
Pubmed: PMID:23622244   (View Abstract at PubMed)
PMCID: PMC3673534   (View Article at PubMed Central)
DOI: DOI:10.1016/j.cell.2013.03.028   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
VDRHumanliver cirrhosis  ISOVdr (Mus musculus) RGD 
VdrRatliver cirrhosis  ISOVdr (Mus musculus) RGD 
VdrMouseliver cirrhosis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Vdr  (vitamin D receptor)

Genes (Mus musculus)
Vdr  (vitamin D (1,25-dihydroxyvitamin D3) receptor)

Genes (Homo sapiens)
VDR  (vitamin D receptor)


Additional Information