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Updated: May 5, 2026
Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein
C M Van Nieuwkerk1, R P Elferink, A K Groen
1Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Background & Aims:
The mouse mdr2 gene encodes a P-glycoprotein expressed in the hepatocanalicular membrane. Inactivation of this gene causes lack of biliary phospholipid and cholesterol secretion and non-suppurative cholangitis. The aim of this study was to investigate the role of bile salt hydrophobicity in induction of liver pathology in mdr2 (-/-) mice.
Methods:
Mice (+/+) wild type or (-/-) knockout for the mdr2 gene were fed with either purified control diet or this diet supplemented with cholate (0.1%) or ursodeoxycholate (0.5%) for 3, 6, or 22 weeks after weaning. Liver histology was semiquantitatively scored.
Results:
Each mouse fed bile acid became the major constituent of the bile salt pool. The cholate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, lever histology had already deteriorated after 3 weeks in the (-/-) mice and caused pronounced inflammatory nonsuppurative cholangitis and fibrosis in the 75% of mice that survived. Dietary ursodeoxycholate had no effect on histology in (+/+) mice but improved liver pathology significantly in (-/-) mice compared with purified control diet; the decrease of ductular proliferation and portal inflammation was most prominent after 22 weeks.
Conclusions:
The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity.
Insights
Bile salt hydrophobicity significantly impacts liver disease in mdr2 knockout mice. Ursodeoxycholate improved liver pathology, suggesting its therapeutic potential for cholangitis.
Area of Science:
- Hepatology
- Molecular Biology
- Gastroenterology
Background:
- The mdr2 gene encodes a P-glycoprotein crucial for biliary lipid secretion.
- Mdr2 gene inactivation leads to phospholipid deficiency and non-suppurative cholangitis.
- This study investigates bile salt hydrophobicity's role in mdr2 knockout mouse liver pathology.
Purpose of the Study:
- To determine the influence of bile salt hydrophobicity on liver disease development in mdr2 knockout mice.
- To assess the impact of cholate and ursodeoxycholate on liver histology in wild-type and mdr2 knockout mice.
Main Methods:
- Wild-type and mdr2 knockout mice were fed control, cholate-supplemented, or ursodeoxycholate-supplemented diets.
- Dietary interventions lasted for 3, 6, or 22 weeks post-weaning.
- Liver histology was evaluated using semiquantitative scoring.
Main Results:
- Cholate-rich diets induced mild pathology in wild-type mice but severe cholangitis and fibrosis in mdr2 knockout mice.
- Ursodeoxycholate-fed mdr2 knockout mice showed significantly improved liver histology compared to controls.
- Ursodeoxycholate reduced ductular proliferation and portal inflammation in mdr2 knockout mice.
Conclusions:
- Cholangitis and its consequences in mdr2 knockout mice are dependent on bile salt hydrophobicity.
- Ursodeoxycholate demonstrates a protective effect against liver pathology in this model.
- Bile salt composition plays a critical role in liver disease pathogenesis.
