TY - JOUR
T1 - The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters
AU - van Golen, Rowan F.
AU - Olthof, Pim B.
AU - de Haan, Lianne R.
AU - Coelen, Robert J.
AU - Pechlivanis, Alexandros
AU - de Keijzer, Mark J.
AU - Weijer, Ruud
AU - de Waart, Dirk R.
AU - van Kuilenburg, André B. P.
AU - Roelofsen, Jeroen
AU - Gilijamse, Pim W.
AU - Maas, Martinus A.
AU - Lewis, Matthew R.
AU - Nicholson, Jeremy K.
AU - Verheij, Joanne
AU - Heger, Michal
PY - 2018
Y1 - 2018
N2 - 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 28days 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
AB - 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 28days 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
U2 - https://doi.org/10.1016/j.bbadis.2017.11.022
DO - https://doi.org/10.1016/j.bbadis.2017.11.022
M3 - Article
C2 - 29196240
SN - 0925-4439
VL - 1864
SP - 942
EP - 951
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 3
ER -