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

被引：16

作者：

van Golen, Rowan F. ^{[1
]}

Olthof, Pim B. ^{[1
]}

de Haan, Lianne R. ^{[1
]}

Coelen, Robert J. ^{[1
]}

Pechlivanis, Alexandros ^{[2
]}

de Keijzer, Mark J. ^{[1
]}

Weijer, Ruud ^{[1
]}

de Waart, Dirk R. ^{[3
]}

van Kuilenburg, Andre B. P. ^{[4
]}

Roelofsen, Jeroen ^{[4
]}

Gilijamse, Pim W. ^{[1
]}

Maas, Martinus A. ^{[1
]}

Lewis, Matthew R. ^{[2
,5
]}

Nicholson, Jeremy K. ^{[2
,5
]}

Verheij, Joanne ^{[6
]}

Heger, Michal ^{[1
,7
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Dept Expt Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[2] Dept Surg & Canc, Div Computat Syst & Digest Med, South Kensington Campus, London SW7 2AZ, England

[3] Univ Amsterdam, Acad Med Ctr, Tytgat Inst Liver & Intestinal Res, Amsterdam, Netherlands

[4] Univ Amsterdam, Acad Med Ctr, Lab Genet Metab Disorders, Amsterdam, Netherlands

[5] Imperial Coll London, Hammersmith Hosp, Dept Surg & Canc, MRC NIHR Natl Phenome Ctr, London W12 0NN, England

[6] Univ Amsterdam, Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands

[7] Univ Utrecht, Inst Biomembranes, Bijvoet Ctr Biomol Res, Membrane Biochem & Biophys, Utrecht, Netherlands

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2018年 / 1864卷 / 03期

基金：

英国医学研究理事会;

关键词：

Cholestasis; Muricholic acid; Cholangiocarcinoma; Bile duct ligation; Hepatostat; Gut-liver axis; Fgf15/FGF19; Liver fibrosis; Cholangiopathy; Cholangiocytes; FARNESOID-X RECEPTOR; GROWTH-FACTOR; 19; PRIMARY BILIARY-CIRRHOSIS; BILE-ACID METABOLISM; DUCT-LIGATED MICE; CHENODEOXYCHOLIC ACID; LIVER-REGENERATION; HUMAN HEPATOCYTES; CELL-DEATH; EXPRESSION;

D O I：

10.1016/j.bbadis.2017.11.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：942 / 951

页数：10

共 57 条

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