A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
Liver fibrosis is a reversible wound-healing response involving TGFbeta1/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 TGFbeta1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFbeta1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFbeta1-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.
|Authors||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.;|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/23622244|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11796|