title: FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis.
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.
authors.affiliation: Division of Liver and Biliopancreatic disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Mannaerts
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Translational Cell and Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Division of Liver and Biliopancreatic disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vander Elst
authors.affiliation: Division of Liver and Biliopancreatic disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos II, Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Farre
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven - University of Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, VIB, Leuven, Belgium.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wenes
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven - University of Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, VIB, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Division of Liver and Biliopancreatic disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Division of Liver and Biliopancreatic disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013853:Thioacetamide; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015415:Biomarkers; D002635:Chenodeoxycholic Acid; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D013853:Thioacetamide; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid