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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Biomarkers / metabolism
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Cell Cycle / drug effects
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Cell Line
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Cell Proliferation / drug effects
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Chenodeoxycholic Acid / analogs & derivatives*
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Chenodeoxycholic Acid / pharmacology
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Chenodeoxycholic Acid / therapeutic use
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Cytokines / metabolism
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Disease Models, Animal
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Hemodynamics / drug effects
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Hepatic Stellate Cells / drug effects
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Hepatic Stellate Cells / metabolism
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Hepatic Stellate Cells / pathology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Inflammation / complications
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Inflammation / drug therapy*
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Inflammation / pathology
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Inflammation / physiopathology
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Inflammation Mediators / metabolism
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Kupffer Cells / drug effects
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Kupffer Cells / metabolism
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Kupffer Cells / pathology
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Lipopolysaccharides / pharmacology
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Liver / pathology*
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Liver Cirrhosis / complications
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Liver Cirrhosis / drug therapy*
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Liver Cirrhosis / pathology
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Liver Cirrhosis / physiopathology
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Male
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Mice
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NF-KappaB Inhibitor alpha / metabolism
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NF-kappa B / metabolism
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Portal Pressure / drug effects
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Thioacetamide
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
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Vascular Resistance / drug effects
Substances
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Biomarkers
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Cytokines
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Inflammation Mediators
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Lipopolysaccharides
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NF-kappa B
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Receptors, Cytoplasmic and Nuclear
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Tumor Necrosis Factor-alpha
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obeticholic acid
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Thioacetamide
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farnesoid X-activated receptor
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Chenodeoxycholic Acid
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NF-KappaB Inhibitor alpha