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

N Ding, TY Ruth, N Subramaniam, MH Sherman… - Cell, 2013 - cell.com
N Ding, TY Ruth, N Subramaniam, MH Sherman, C Wilson, R Rao, M Leblanc, S Coulter…
Cell, 2013cell.com
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) …
Summary
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.
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