Journal
CELL
Volume 153, Issue 3, Pages 601-613Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.03.028
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Funding
- Genentech Foundation
- National Institutes of Health [DK057978, HL105278, DK090962, HL088093, ES010337, CA014195]
- National Health and Medical Research Council of Australia [512354, 632886]
- Helmsley Charitable Trust
- Samuel Waxman Cancer Research Foundation
- Ipsen/Biomeasure
- Stand Up to Cancer Dream Team translational cancer research grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]
- [K08HL092298]
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Liver fibrosis is a reversible wound-healing response involving TGF beta 1/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 TGF beta 1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGF beta 1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGF beta 1-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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