3A). The number of T cells in the portal tracts Enzalutamide in vitro of the Mdr2-KO/B6 mice did not change significantly with age, whereas it significantly increased from the first to second month and was still high in the third month in the Mdr2-KO/FVB livers (Fig. 3B). The number of neutrophils in the portal tracts of the Mdr2-KO/B6 mice was not altered with age, whereas it increased from the second to the third month in the Mdr2-KO/FVB livers

(Fig. 3C). We previously demonstrated an increased liver-to-body weight index (LBI) and increased cyclin D1 levels in the hepatocyte nuclei of Mdr2-KO/FVB mice at the age of 3 months.2, 4 Here we found that in the Mdr2-KO/FVB strain, a constant LBI was already established at 2 months of age, whereas in the Mdr2-KO/B6 strain, LBI sharply decreased between 2 and 3 months of age (Fig. 3D). Bromodeoxyuridine (BrdU) incorporation into hepatocytes of both strains dropped significantly between 1 and 2 months of age for the Mdr2-KO mice and the control Mdr2+/− mice (Fig. 3E and Supporting Fig. 2). However, in the Mdr2-KO/FVB mice, BrdU incorporation was similarly increased in a significant manner in comparison with controls at 2 and 3 months of age,

whereas in the Mdr2-KO/B6 mice, it was barely increased at 2 months, and it was not further elevated at 3 months of age (Fig. 3E). Nuclear levels of cyclin D1 in hepatocytes decreased gradually with age in Mdr2-KO and control Mdr2+/− livers of both strains (Fig. 3F and Supporting Fig. 3), and they were particularly higher in the Mdr2-KO livers. In the Mdr2-KO/B6 mice, nuclear localization of cyclin D1 in hepatocytes check details dropped significantly between 2 and 3 months of age (Fig. 3F). There was low and equivalent hepatocyte apoptosis in mutant and control livers at all ages tested (Supporting Fig. 4). Thus, at 2 months of age, hepatocyte proliferation and LBI were similarly increased in both Mdr2-KO mutants, whereas medchemexpress at 3 months of age, these parameters were significantly reduced in the Mdr2-KO/B6

strain. To dissect the mechanisms responsible for the attenuation of chronic liver disease in the Mdr2-KO/B6 mice at the age of 3 months, we performed a genome-scale gene expression profiling analysis of liver tissues from the Mdr2-KO and control Mdr2+/− B6 males with Affymetrix microarrays. We compared genes that were aberrantly expressed in Mdr2-KO livers from the B6 strain (our current study) and the FVB strain (our previous study4) with the same GCRMA algorithm. This comparative analysis revealed a striking difference between up-regulated and down-regulated genes in the Mdr2-KO mutants of both strains: there were approximately 3.8-fold more up-regulated genes in the FVB strain versus the B6 strain, whereas for down-regulated genes, there was only about a 20% difference between the strains (Fig. 4A,B).