Hepatic Iron Accumulation is Reduced in the Cholestatic Mdr2-/- Mouse

The multidrug-resistance 2 (Mdr2-/-) mouse is an animal model of biliary liver injury and fibrosis. This genetic equivalent of the human disorder progressive familial intrahepatic cholestasis type 3 histologically resembles primary sclerosing cholangitis. Bile acid accumulation during cholestasis is linked to the downregulation of the iron regulatory hormone hepcidin, thus suggesting a link between liver disease and iron homeostasis. In this study we investigated iron homeostasis in the Mdr2-/-mouse model of cholestasis. Iron levels and expression of iron-related genes were analysed by real-time PCR and western blotting. Accumulation of iron and the hepcidin response were analysed in wild-type and Mdr2-/- mice challenged with either an iron-deficient or a 1% carbonyl iron diet. Mdr2-/-mice on a control diet had reduced hepatic iron stores when compared to age-matched controls, despite lower hepatic hepcidin expression, and a corresponding elevation in hepatic transferrin receptor 1 expression. Mdr2-/-mice fed a 1% carbonyl iron diet were resistant to hepatic iron accumulation, despite increased serum iron, suggesting impaired hepatocyte iron uptake in this model. In conclusion, Mdr2-/- have abnormal hepatic iron homeostasis, potentially resulting from cholestasis. Impaired hepatic iron uptake may explain the relative paucity of liver iron in cholestatic compared to hepatocellular conditions.