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

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.
Authors	Ning Ding, Ruth T Yu, Nanthakumar Subramaniam, Mara H Sherman, Caroline Wilson, Renuka Rao, Mathias Leblanc, Sally Coulter, Mingxiao He, Christopher Scott, Sue L Lau, Annette R Atkins, Grant D Barish, Jenny E Gunton, Christopher Liddle, Michael Downes, Ronald M Evans
Journal	Cell (Cell) Vol. 153 Issue 3 Pg. 601-13 (Apr 25 2013) ISSN: 1097-4172 [Electronic] United States
PMID	23622244 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2013 Elsevier Inc. All rights reserved.
Chemical References	Receptors, Calcitriol Smad3 Protein Smad3 protein, mouse Transforming Growth Factor beta1 calcipotriene Calcitriol
Topics	Animals Calcitriol (analogs & derivatives) Fibrosis (prevention & control) Gene Regulatory Networks Genome-Wide Association Study Hepatic Stellate Cells Liver (injuries, metabolism, pathology) Male Mice Mice, Inbred C57BL Mice, Knockout Rats Receptors, Calcitriol (agonists, metabolism) Signal Transduction Smad3 Protein (metabolism) Transcriptome Transforming Growth Factor beta1 (metabolism)

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