The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
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]
In the citing paper
“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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Cites
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
Bataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958
Cellular and molecular mechanisms of fibrosis
Wynn, T. (2008) · The Journal of Pathology · doi:10.1002/path.2277 · Cited by 4,495
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842
Smad transcription factorsPreprint
Massagué, J., Seoane, J., & Wotton, D. (2005) · Genes & Development · doi:10.1101/gad.1350705 · Cited by 2,519
Nuclear Receptors and Lipid Physiology: Opening the X-Files
Chawla, A., Repa, J. J., Evans, R. M., & Mangelsdorf, D. J. (2001) · Science · doi:10.1126/science.294.5548.1866 · Cited by 2,085
Self-citationTLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942
Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis
Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S., & Ascherio, A. (2006) · JAMA · doi:10.1001/jama.296.23.2832 · Cited by 1,899
SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS
Feng, X.-H., & Derynck, R. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.022404.142018 · Cited by 1,869
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Remodelling the extracellular matrix in development and disease
Bonnans, C., Chou, J., & Werb, Z. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3904 · Cited by 4,367
Mechanisms of hepatic stellate cell activation
Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909
Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects
Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L., & Carmeliet, G. (2015) · Physiological Reviews · doi:10.1152/physrev.00014.2015 · Cited by 2,105
Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis
Jia, W., Xie, G., & Jia, W. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.119 · Cited by 1,924
Hepatic stellate cells as key target in liver fibrosis
Higashi, T., Friedman, S. L., & Hoshida, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.007 · Cited by 1,485
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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