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

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 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.

Finding fibroblast growth factor 19 during cholestasis: Does x mark the spot?

“…4 Patients with primary biliary cholangitis (PBC) also have increased serum FGF19, hepatic FGF19 gene and protein expression. 5 In contrast to the expression pattern in alcoholic hepatitis and biliary cirrhosis, FGF19 co-localized with FGFR4 suggesting a predominant expression in hepatocytes. 5 Co-localization with other non-parenchymal liver cell markers was not performed.…”

Exploring the Potential Mechanisms of Action of Gentiana Veitchiorum Hemsl. Extract in the Treatment of Cholestasis using UPLC-MS/MS, Systematic Network Pharmacology, and Molecular Docking

“…Cholestasis is a clinical syndrome caused by defective secretion, absorption, and ow of bile, resulting in retention of bile components in the liver and serum [39]. The condition, which is most commonly seen in patients with liver diseases such as primary cholangitis, primary sclerosing cholangitis and viral hepatitis, may be caused by a variety of factors, including toxic compounds, drug-induced liver injury, disease (viral hepatitis, bile duct obstruction, sepsis, cholelithiasis), genetic abnormalities (progressive familial intrahepatic cholestasis) and disorders of the intestinal microbiota [40].…”

A physiologically based model of bile acid metabolism in mice

“…Investigating the link between BA metabolism and their role in human disease, various animal models have been applied, including lamprey, skate, zebrafish, rat, mouse, hamster, rabbit, prairie dog, and monkey. 59 , 60 , 61 Of the small animal models, hamsters are most similar to humans regarding BA metabolism 62 , 63 , 64 ; nevertheless, mice remain the most commonly utilized animal model to investigate human metabolism. 17 , 18 Indicative of the difference between human and mice is the different bile acid composition.…”