期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1864, 期 3, 页码 942-951出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2017.11.022
关键词
Cholestasis; Muricholic acid; Cholangiocarcinoma; Bile duct ligation; Hepatostat; Gut-liver axis; Fgf15/FGF19; Liver fibrosis; Cholangiopathy; Cholangiocytes
资金
- AMC PhD Scholarship from the Academic Medical Center in Amsterdam
- Young Talent Fund from the Academic Medical Center in Amsterdam
- Stichting Technologische Wetenschap [12064]
- Koningin Wilhelmina Fonds [10666]
- Stichting Nationaal Fonds Tegen Kanker in Amsterdam (SNFKHeger)
- Phospholipid Research Center in Heidelberg (PRCHeger)
- Nijbakker-Morra Foundation in Leiden (project NMSHeger)
- Medical Research Council
- National Institute for Health Research [MC_PC_12025]
- MRC [MC_PC_12025] Funding Source: UKRI
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.
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