| Institution: | 1. Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;2. Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK;3. Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;4. Laboratory Genetic Metabolic Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;5. MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK;6. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;7. Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands |
| Abstract: | Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28 days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease. |
