FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
Open accessAbstract
Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro , OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis.
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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 [38]
FXR agonists have shown anti-fibrotic/cirrhotic effects in several rodent models, including CCl4 and TAA poison, BDL, porcine serum injection, and NASH.
“FXR agonists have shown anti-fibrotic/cirrhotic effects in several rodent models, including CCl4 and TAA poison, BDL, porcine serum injection, and NASH38,49.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [38]
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- Authors
- Verbeke, L., Mannaerts, I., Schierwagen, R., Govaere, O., Klein, S., Vander Elst, I., Windmolders, P., Farre, R., Wenes, M., Mazzone, M., Nevens, F., van Grunsven, L. A., Trebicka, J., & Laleman, W.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Vrije Universiteit Brussel (BE)
- University of Bonn (DE)
- KU Leuven (BE)
- Corresponding author
- Verbeke, Len
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-09-16
- Volume
- 6
- Issue
- 1
- Pages
- 33453-33453
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5025787
- OpenAlex
- W2519114186
- Cited by
- 236
- References
- 53
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 23 · 2023: 13 · 2022: 28 · 2021: 32 · 2020: 28 · 2019: 25 · 2018: 20 · 2017: 21 · 2016: 4
- FWCI
- 16.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Lirias (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Intercept Pharmaceuticals
- Deutsche Forschungsgemeinschaft (TRR57, project 18, SFB‐TRR57, SFB TRR57 project 18)
- Belgian Federal Science Policy Office (P7/47)
- Fonds Wetenschappelijk Onderzoek (12N5415N LV, 12N5415N)
- Vrije Universiteit Brussel (GOA78, OZR1930)
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- obeticholic acid, farnesoid X receptor agonist, liver cirrhosis, liver inflammation, liver fibrosis, hepatic stellate cell activation, thioacetamide-induced liver injury, NF-κB signaling, IκBα, Kupffer cells, liver sinusoidal endothelial cells, profibrotic cytokines, portal hypertension, hepatocyte turnover
- MeSH terms
- NF-KappaB Inhibitor alpha, Receptor, Farnesoid X-Activated, Animals, Cell Cycle, Cell Line, Chenodeoxycholic Acid, Disease Models, Animal, Hemodynamics, Humans, Inflammation, Kupffer Cells, Lipopolysaccharides, Liver, Liver Cirrhosis, Male, Thioacetamide, Tumor Necrosis Factor-alpha, Vascular Resistance, Biomarkers, Up-Regulation, Cytokines, NF-kappa B, Portal Pressure, Rats, Wistar, Apoptosis, Receptors, Cytoplasmic and Nuclear, Inflammation Mediators, Hepatocytes, Endothelial Cells, Cell Proliferation, Mice, Hepatic Stellate Cells
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