Title: FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
Authors: Verbeke, Len ×
Mannaerts, Inge
Schierwagen, Robert
Govaere, Olivier
Klein, Sabine
Vander Elst, Ingrid
Windmolders, Petra
Farre, Ricard
Wenes, Mathias
Mazzone, Max
Nevens, Frederik
van Grunsven, Leo A
Trebicka, Jonel
Laleman, Wim #
Issue Date: 2016
Series Title: Scientific Reports vol:6
Article number: 10.1038/srep33453
Abstract: 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.
ISSN: 2045-2322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Tumor Inflammation and Angiogenesis (Vesalius Research Center) (+)
Translational Research in GastroIntestinal Disorders
Translational Cell & Tissue Research
× corresponding author
# (joint) last author

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