Cross-Talk between Farnesoid-X-Receptor (FXR) and Peroxisome Proliferator-Activated Receptor γ Contributes to the Antifibrotic Activity of FXR Ligands in Rodent Models of Liver Cirrhosis
Abstract
The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPARgamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPARgamma mRNA by approximately 40-fold. Submaximally effective concentrations of FXR and PPARgamma ligands were additive in inhibiting alpha1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARgamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARgamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGFbeta1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARgamma and uncoupling protein 2, a PPARgamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARgamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARgamma cascade exerts counter-regulatory effects in HSCs activation.
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Various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models.
“Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [36]
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References 31 · Cited by 177
- Authors
- Fiorucci, S., Rizzo, G., Antonelli, E., Renga, B., Mencarelli, A., Riccardi, L., Morelli, A., Pruzanski, M., & Pellicciari, R.
- Affiliations
- University of Perugia (IT)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 315
- Issue
- 1
- Pages
- 58-68
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2150024800
- Cited by
- 177
- References
- 31
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 12 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 13 · 2014: 8 · 2013: 5 · 2012: 8
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- farnesoid X receptor, PPARγ, liver fibrosis, liver cirrhosis, hepatic stellate cells, rosiglitazone, antifibrotic activity, alpha1(I) collagen, TGF-β1, bile duct ligation, carbon tetrachloride, porcine serum, UCP2, tissue inhibitors of metalloproteinases
- MeSH terms
- Rosiglitazone, Receptor, Farnesoid X-Activated, Animals, Cells, Cultured, Chenodeoxycholic Acid, DNA-Binding Proteins, Gene Expression Regulation, Humans, Liver, Liver Cirrhosis, Experimental, RNA, Messenger, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Thiazolidinediones, PPAR gamma, Rats
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