Mouse models of cholestatic liver disease: PFIC revisited

Progressive familial intrahepatic cholestasis (PFIC) is a severe inherited form of cholestasis. This disease consists of 3 types (PFIC1-3) and is caused by mutations in ATP8B1, ABCB11 and ABCB4, respectively. All these genes encode for transport proteins in the canalicular membrane of the hepatocyte that are involved in proper bile formation. In the past mouse models for all 3 forms of PFIC were studied and revealed a mild phenotype compared to human patients. This difference is most likely due to a difference in bile salt hydrophobicity between mice and men and therefore toxicity. In this thesis a new mouse model with reduced bile salt hydroxylation capacity was studied in order to create a more human like mouse model for cholestasis. After backcrossing this new mouse model with existing mouse models for either PFIC1 or PFIC3 a more severe form of cholestasis was seen compared to the single mutant mice. Furthermore this thesis shows the ameliorating effect of bile salt feeding on hepatic steatosis in a mouse model with reduced bile salt pool.