Cited by 622Liver physiology and pathologyTGF-β signaling in diseasesLiver Diseases and Immunity

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

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Ding, Ning, Yu, Ruth T., Subramaniam, Nanthakumar, Sherman, Mara H., Wilson, Caroline, Rao, Renuka, Leblanc, Mathias, Coulter, Sally +9 more·2013·Cell

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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Crossref · 10.1016/j.cell.2013.03.028

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  • VDR -/- mice developed spontaneous liver fibrosis, indicating the importance of VDR in liver fibrosis and showing that VDR signaling regulates inhibition of hepatic stellate cell activation.

    “In an animal study, VDR -/-mice developed spontaneous liver fibrosis, thus indicating the importance of VDR in liver fibrosis and showing that VDR signaling regulates the inhibition of HSC activation.[95]”

    From Nuclear receptors in liver fibrosis (2021) · cites this paper as [95]

  • VDR activation inhibits signaling of a TGF-β/SMAD-dependent transcription response in hepatic stellate cells.

    “Briefly, VDR activation inhibits the signaling of a TGF-β/SMAD-dependent transcription response in HSCs.[95]”

    From Nuclear receptors in liver fibrosis (2021) · cites this paper as [95]

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Authors
Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., Lau, S. L., Atkins, A. R., Barish, G. D., Gunton, J. E., Liddle, C., Downes, M., & Evans, R. M.
Affiliations
  • Salk Institute for Biological Studies (US)
  • The University of Sydney (AU)
  • Garvan Institute of Medical Research (AU)
Corresponding author
  • Downes, Michael
  • Evans, Ronald M.
Venue
Cell
Publisher
Elsevier BV
Published
2013-04
Volume
153
Issue
3
Pages
601-613
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2144378498
Cited by
622
References
68
Citations by year
2026: 26 · 2025: 24 · 2024: 38 · 2023: 51 · 2022: 39 · 2021: 48 · 2020: 57 · 2019: 54 · 2018: 52 · 2017: 55 · 2016: 57 · 2015: 53 · 2014: 49 · 2013: 19
FWCI
37.00
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Heart, Lung, and Blood Institute (HL105278, K08HL092298, R01HL105278, HL-088093, P01HL088093)
  • National Cancer Institute (CA014195, T32CA009370, P30CA014195, P30CA060553)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK057978, R01DK057978, R24DK090962, DK090962, P30DK063491)
  • National Institute of Environmental Health Sciences (P42ES010337, ES 010337)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
vitamin D receptor, Smad3, liver fibrosis, hepatic stellate cells, TGF-β1 signaling, chromatin remodeling, fibrogenesis, wound healing, extracellular matrix deposition, VDR knockout mice
MeSH terms
Animals, Calcitriol, Fibrosis, Liver, Male, Mice, Inbred C57BL, Signal Transduction, Receptors, Calcitriol, Mice, Knockout, Mice, Rats, Smad3 Protein, Gene Regulatory Networks, Transforming Growth Factor beta1, Genome-Wide Association Study, Hepatic Stellate Cells, Transcriptome

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