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A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response
Open accessAbstract
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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“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]
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“Briefly, VDR activation inhibits the signaling of a TGF-β/SMAD-dependent transcription response in HSCs.[95]”
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Metadata
- 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.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 153
- Issue
- 3
- Pages
- 601-613
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3673534
- 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
- bronze
- doi.org
- Licence
- 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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