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.
BACKGROUND & AIMS: The mousemdr2 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.
Authors: James H Tabibian; Steven P O'Hara; Christy E Trussoni; Pamela S Tietz; Patrick L Splinter; Taofic Mounajjed; Lee R Hagey; Nicholas F LaRusso Journal: Hepatology Date: 2015-08-10 Impact factor: 17.425
Authors: Renxue Wang; Jonathan A Sheps; Lin Liu; Jun Han; Patrick S K Chen; Jason Lamontagne; Peter D Wilson; Ian Welch; Christoph H Borchers; Victor Ling Journal: J Lipid Res Date: 2018-11-11 Impact factor: 5.922
Authors: Anuradha Krishnan; Tomohiro Katsumi; Maria E Guicciardi; Adiba I Azad; Nazli B Ozturk; Christy E Trussoni; Gregory J Gores Journal: Am J Pathol Date: 2020-03-30 Impact factor: 4.307
Authors: Aleksandar Sokolović; Milka Sokolović; Willem Boers; Ronald Pj Oude Elferink; Piter J Bosma Journal: Fibrogenesis Tissue Repair Date: 2010-02-17