Comprehensive phenotypic characterization of ABCB4 deficient mice reveals systemic effects of spontaneous biliary fibrosis

Aims: ABCB4 deficiency in humans causes or contributes to chronic cholestatic liver diseases. The progression of liver diseases related to ABCB4 deficiency and their systemic effects differ significantly between individuals, yet the genetic factors contributing to these mechanisms are unknown. Our aim now was to phenotypically characterize immune and extrahepatic phenotypes in a genetically defined model of spontaneous biliary fibrosis. Methods: We generated congenic mice by introgressing the Abcb4 knockout from the FVB/NJ strain into the fibrosis-susceptible BALB/cJ background for 10 generation. At the age of 16 weeks, 20 female and 20 male BALB-Abcb4-/- mice and 40 wild-type control mice (BALB/cJ) were phenotyped in standardized, comprehensive workflows (German Mouse Clinic. Nat Methods 2005;2: 403). Results: Clinical-chemical data displayed elevated serum liver enzymes (ALT, AST, AP) in Abcb4-/- mice, whereas serum lipid levels (triglycerides, free fatty acid, cholesterol) were significantly decreased. Erythrocytes displayed a mild hypochromic and microcytic differentiation, whereas white blood cell counts were elevated. Of note, FACS analysis of leukocytes revealed a lower proportion of granulocytes and a higher proportion of T-lymphocytes in Abcb4-/- mice. Detailed analysis of CD4+ and CD8+ T- lymphocytes in peripheral blood showed significant differences of distinct subpopulations, e.g. levels of Ly6C+ CD44+ CD25- cells were decreased and levels of Ly6C- CD44+ CD25- CD4+ cells were increased, whereas CD8+ cells displayed inverse alterations. Conclusions: Comprehensive phenotypic characterization of BALB-Abcb4-/- deficient mice identified systemic alterations of peripheral blood and immune cell populations. Since we did not observe signs of persistent infection, these changes are likely to reflect the systemic immune response to chronic cholestatic liver injury in this mouse model. Supported by NGFN German Mouse Clinic

Abcb4 - liver fibrosis - mdr2