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

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          Abstract

          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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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          1097-4172
          0092-8674
          Apr 25 2013
          : 153
          : 3
          Affiliations
          [1 ] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
          Article
          S0092-8674(13)00350-4 NIHMS474458
          10.1016/j.cell.2013.03.028
          3673534
          23622244
          8aa9b022-b801-44ec-b38e-7021150277cf
          Copyright © 2013 Elsevier Inc. All rights reserved.
          History

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