Cited by 259Liver Disease and TransplantationLiver physiology and pathologyLiver Disease Diagnosis and Treatment

Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats

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Verbeke, Len, Farre, Ricard, Trebicka, Jonel, Komuta, Mina, Roskams, Tania, Klein, Sabine, Elst, Ingrid Vander, Windmolders, Petra +3 more·2014·Hepatology

Abstract

The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct–ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro . FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2. Conclusion : FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis. (Hepatology 2014;59:2286–2298)

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Authors
Verbeke, L., Farre, R., Trebicka, J., Komuta, M., Roskams, T., Klein, S., Elst, I. V., Windmolders, P., Vanuytsel, T., Nevens, F., & Laleman, W.
Affiliations
  • Universitair Ziekenhuis Leuven (BE)
  • University of Bonn (DE)
  • KU Leuven (BE)
Corresponding author
Verbeke, Len
Venue
Hepatology
Published
2014-06
Volume
59
Issue
6
Pages
2286-2298
ISSN
0270-9139 (ISSN-L)
OpenAlex
W2067719505
Cited by
258
References
55
Citations by year
2026: 4 · 2025: 12 · 2024: 14 · 2023: 14 · 2022: 27 · 2021: 27 · 2020: 17 · 2019: 30 · 2018: 27 · 2017: 20 · 2016: 30 · 2015: 21 · 2014: 15
FWCI
13.65
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
obeticholic acid, farnesoid X receptor, cirrhotic portal hypertension, hepatic vascular resistance, endothelial nitric oxide synthase, Rho kinase, dimethylarginine dimethylaminohydrolase, hepatic stellate cells, endothelial dysfunction, bile duct ligation, thioacetamide-induced liver injury, hepatic hemodynamics
MeSH terms
Receptor, Farnesoid X-Activated, Animals, Chenodeoxycholic Acid, Disease Models, Animal, Drug Evaluation, Preclinical, Hypertension, Portal, Liver Cirrhosis, Male, Random Allocation, Signal Transduction, Down-Regulation, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Rats, Nitric Oxide Synthase Type III

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