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FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

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 to...

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Autores principales: Verbeke, Len, Mannaerts, Inge, Schierwagen, Robert, Govaere, Olivier, Klein, Sabine, Vander Elst, Ingrid, Windmolders, Petra, Farre, Ricard, Wenes, Mathias, Mazzone, Massimiliano, Nevens, Frederik, van Grunsven, Leo A., Trebicka, Jonel, Laleman, Wim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025787/
https://www.ncbi.nlm.nih.gov/pubmed/27634375
http://dx.doi.org/10.1038/srep33453
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author Verbeke, Len
Mannaerts, Inge
Schierwagen, Robert
Govaere, Olivier
Klein, Sabine
Vander Elst, Ingrid
Windmolders, Petra
Farre, Ricard
Wenes, Mathias
Mazzone, Massimiliano
Nevens, Frederik
van Grunsven, Leo A.
Trebicka, Jonel
Laleman, Wim
author_facet Verbeke, Len
Mannaerts, Inge
Schierwagen, Robert
Govaere, Olivier
Klein, Sabine
Vander Elst, Ingrid
Windmolders, Petra
Farre, Ricard
Wenes, Mathias
Mazzone, Massimiliano
Nevens, Frederik
van Grunsven, Leo A.
Trebicka, Jonel
Laleman, Wim
author_sort Verbeke, Len
collection PubMed
description 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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spelling pubmed-50257872016-09-22 FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis Verbeke, Len Mannaerts, Inge Schierwagen, Robert Govaere, Olivier Klein, Sabine Vander Elst, Ingrid Windmolders, Petra Farre, Ricard Wenes, Mathias Mazzone, Massimiliano Nevens, Frederik van Grunsven, Leo A. Trebicka, Jonel Laleman, Wim Sci Rep Article 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. Nature Publishing Group 2016-09-16 /pmc/articles/PMC5025787/ /pubmed/27634375 http://dx.doi.org/10.1038/srep33453 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Verbeke, Len
Mannaerts, Inge
Schierwagen, Robert
Govaere, Olivier
Klein, Sabine
Vander Elst, Ingrid
Windmolders, Petra
Farre, Ricard
Wenes, Mathias
Mazzone, Massimiliano
Nevens, Frederik
van Grunsven, Leo A.
Trebicka, Jonel
Laleman, Wim
FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title_full FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title_fullStr FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title_full_unstemmed FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title_short FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
title_sort fxr agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025787/
https://www.ncbi.nlm.nih.gov/pubmed/27634375
http://dx.doi.org/10.1038/srep33453
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