The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters

Rowan F van Golen, Pim B Olthof, Lianne R de Haan, Robert-Jan Coelen, Alexandros Pechlivanis, Mark J de Keijzer, Ruud Weijer, Dirk R de Waart, André B P van Kuilenburg, Jeroen Roelofsen, Pim W Gilijamse, Martinus A Maas, Matthew R Lewis, Jeremy K Nicholson, Joanne Verheij, Michal Heger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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, and suppression of BA production. 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.

Original languageEnglish
Pages (from-to)942-951
JournalBiochimica et Biophysica Acta
Volume1864
Issue number3
Early online date28 Nov 2017
DOIs
Publication statusPublished - Mar 2018

Keywords

  • Cholestasis
  • Muricholic acid
  • Cholangiocarcinoma
  • Bile duct ligation
  • Hepatostat
  • Gut-liver axis
  • Fgf15/FGF19
  • Liver fibrosis
  • Cholangiopathy
  • Cholangiocytes

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