| First Author | Ding N | Year | 2013 |
| Journal | Cell | Volume | 153 |
| Issue | 3 | Pages | 601-13 |
| PubMed ID | 23622244 | Mgi Jnum | J:198440 |
| Mgi Id | MGI:5496743 | Doi | 10.1016/j.cell.2013.03.028 |
| Citation | Ding N, et al. (2013) A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153(3):601-13 |
| abstractText | 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. |
