Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids
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Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9-cis RA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All-trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli. (Hepatology 2004;39:97-108.)
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Hellemans et al. showed a difference in the phenotype of HSCs depending on the presence of natural or synthetic retinoids.
“Additionally, Hellemans et al. showed a difference in the phenotype of HSCs depending on the presence of natural or synthetic retinoids, which might explain divergent results by prior studies.[177]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [177]
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- Authors
- Hellemans, K., Verbuyst, P., Quartier, E., Schuit, F., Rombouts, K., Chandraratna, R. A. S., Schuppan, D., & Geerts, A.
- Affiliations
- Vrije Universiteit Brussel (BE)
- Allergan (United States) (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Hellemans, Karine
- Geerts, Albert
- Venue
- Hepatology
- Published
- 2004-01
- Volume
- 39
- Issue
- 1
- Pages
- 97-108
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2031907605
- Cited by
- 102
- References
- 63
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 6 · 2021: 9 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 7 · 2014: 5 · 2013: 3 · 2012: 2
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- hepatic stellate cells, stellate cell activation, liver fibrosis, retinoic acid, retinoid X receptor, retinoic acid receptor, 9-cis-retinoic acid, all-trans retinoic acid, collagen synthesis, fibronectin, cell proliferation, retinoic acid signaling
- MeSH terms
- Alitretinoin, Amino Acid Sequence, Animals, Antineoplastic Agents, Base Sequence, Benzoates, Cell Division, Fatty Acids, Unsaturated, Liver, Liver Cirrhosis, Male, Molecular Sequence Data, Phenotype, Retinoids, RNA, Messenger, Tetrahydronaphthalenes, Transcription Factors, Tretinoin, Gene Expression, Extracellular Matrix Proteins, Rats, Wistar, Receptors, Retinoic Acid, Dimerization, Retinoid X Receptors, Rats
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