Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene

C. M J Van Nieuwkerk, R. P J O Elferink, A. K. Groen, R. Ottenhoff, G. N J Tytgat, K. P. Dingemans, M. A. Van den Bergh Weerman, G. J A Offerhaus

Research output: Contribution to journalArticlepeer-review

Abstract

Background and 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 chelate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, liver 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.

Original languageEnglish (US)
Pages (from-to)165-171
Number of pages7
JournalGastroenterology
Volume111
Issue number1
DOIs
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

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