@article{740ca078ebb64a9086856e7e7a653e1b,
title = "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.",
author = "Ning Ding and Yu, {Ruth T.} and Nanthakumar Subramaniam and Sherman, {Mara H.} and Caroline Wilson and Renuka Rao and Mathias Leblanc and Sally Coulter and Mingxiao He and Christopher Scott and Lau, {Sue L.} and Atkins, {Annette R.} and Barish, {Grant D.} and Gunton, {Jenny E.} and Christopher Liddle and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: We thank C. Brondos and E. Ong for administrative assistance, J. Nery for assistance with DNA sequencing, C. Benner for assistance with HOMER software, and H. Juguilon and J. Alvarez for technical assistance. N.D. was supported by a postdoctoral fellowship from Genentech Foundation. G.D.B. was supported by grant K08HL092298. This work was funded by grants from the National Institutes of Health (DK057978, HL105278, DK090962, HL088093, ES010337, and CA014195) and National Health and Medical Research Council of Australia project grants 512354 and 632886 (to C.L. and M.D.), as well as by the Helmsley Charitable Trust, Samuel Waxman Cancer Research Foundation, and Ipsen/Biomeasure. R.M.E. and M.D. are supported in part by a Stand Up to Cancer Dream Team translational cancer research grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509). R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes chair in molecular and developmental biology at the Salk Institute. ",
year = "2013",
month = apr,
day = "25",
doi = "10.1016/j.cell.2013.03.028",
language = "English (US)",
volume = "153",
pages = "601--613",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}