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Peroxisome proliferator-activated receptor γ transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells
Open accessAbstract
During liver injury, hepatic stellate cells (HSC) acquire a myofibroblast-like phenotype associated with reduction of lipid droplets, increased collagen synthesis, and proliferation. Peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and controls gene transcription in response to various activators including prostanoids and antidiabetic thiazolidinediones. We explored whether the presence of PPARγ and its transcriptional activity were involved in control of HSC proliferation in vitro. PPARγ ligands, 15-deoxy-△12 14 prostaglandin J 2 (15d-PGJ 2) and ciglitizone, significantly decrease platelet-derived growth factor (PDGF)-induced proliferation in activated human HSC and inhibit α smooth muscle actin (α-SMA) expression during HSC transdifferentiation. Treatment with 9-cis retinoic acid (9-cisRA) and LG268, ligands of the heterodimerization partner retinoic X receptor (RXR), had a negligible effect in PDGF-treated cells but caused a further reduction of proliferation when used in combination with ciglitizone. Transfection experiments with a reporter gene consisting of 3 copies of a PPAR response element (peroxisome proliferator response element [PPRE]3-tk-luciferase) showed a progressive reduction of PPAR transcriptional activity during plastic-induced HSC transdifferentiation. Cotransfection with human PPARγ expression vector restored the PPRE 3-tk-luciferase reporter expression and the increased level of the receptor in activated HSC-inhibited cell proliferation in a dose-dependent manner. Incubation of human PPARγ-cotransfected HSC with PDGF strongly inhibited luciferase activity and this effect was blocked by the inhibition of the mitogen-activated protein (MAP) kinase signal cascade. Our results indicate that depression of PPARγ expression and activity is involved in HSC proliferation and that the PPARγ ligand-mediated activation exerts a previously unrecognized inhibition of PDGF-induced mitogenesis in activated human HSC.
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“Interestingly, in vitro studies investigating PPAR-γ activation in HSCs showed an additional decrease of HSC proliferation after PDGFinduction.[129,134]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [134]
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Metadata
- Authors
- Galli, A., Crabb, D., Price, D., Ceni, E., Salzano, R., Surrenti, C., & Casini, A.
- Affiliations
- University of Florence (IT)
- Indiana University Indianapolis (US)
- Corresponding author
- Casini, Alessandro
- Venue
- Hepatology
- Published
- 2000-01
- Volume
- 31
- Issue
- 1
- Pages
- 101-108
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2118881723
- Cited by
- 197
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 7 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 5 · 2012: 9
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- PPARγ, hepatic stellate cells, platelet-derived growth factor, cell proliferation, alpha-smooth muscle actin, retinoic acid, MAPK signaling, liver fibrosis, transcriptional regulation
- MeSH terms
- Cell Differentiation, Cell Division, Cells, Cultured, Gene Expression Regulation, Humans, Liver, Platelet-Derived Growth Factor, RNA, Messenger, Thiazoles, Transcription Factors, Transcription, Genetic, Transfection, Prostaglandin D2, Gene Expression, Receptors, Cytoplasmic and Nuclear, Thiazolidinediones
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