Remarkably, we revealed a significant down-regulation of the Mat1a protein specifically in the livers of Mdr2-KO/FVB mice (Fig. 6A,B). The Mat enzyme catalyzes the synthesis of S-adenosyl methionine, a universal donor of the methyl group for all methylation reactions in the cell. It is encoded by the genes Mat1a and Mat2a/2b; patients with liver cirrhosis have reduced activity of this enzyme.34 Mat1a

is highly expressed in the adult liver and keeps hepatocytes in a quiescent state. In human liver cancer, Mat1a expression is reduced, whereas Mat2a is increased; this switch facilitates cancer cell growth.35 We demonstrated previously that most hepatocytes of the Mdr2-KO/FVB strain undergo cell cycle arrest between the ages 3 and 9 months, www.selleckchem.com/products/Gemcitabine-Hydrochloride(Gemzar).html and this is characterized by a high level of cyclin D1 in hepatocyte nuclei.4, 36 Our current findings demonstrate that selectively in the Mdr2-KO/FVB mice, this stage of hepatocyte cycle arrest is characterized by a decreased level of the www.selleckchem.com/products/otx015.html Mat1a protein and up-regulation of the Mat2b transcript (Supporting Table 2). Despite the inverse differential expression of the Mbd1 transcript in the two Mdr2-KO strains (Supporting Table 2), protein expression

in both strains was increased in the mutant liver versus the control liver (Fig. 5). The Mbd1 protein binds methylated DNA and functions mainly as a transcriptional repressor;

its higher level in the Mdr2-KO/B6 strain versus the Mdr2-KO/FVB strain could be one of the factors responsible for a significantly lower number of up-regulated genes in the former mutant. Published data on the genotypic and phenotypic differences between the B6 and FVB strains are summarized in Supporting Table 4. There are several known differences between these strains that could be responsible check details for the different courses of chronic hepatitis and HCC development in the two Mdr2-KO mutants. The most prominent among them are (1) a deficiency of complement C5 protein in the FVB strain, (2) mutations in mitochondrial DNA in the FVB strain, and (3) a Tnfaip3 (A20) polymorphism that is responsible for the less effective feedback suppression of Tnf-α–induced NF-κB activation in the B6 strain (see the references in Supporting Table 4). In conclusion, we have demonstrated that the B6 murine strain has a remarkable resistance to both chronic hepatitis and HCC development caused by the Mdr2-KO mutation. By a comparative analysis of liver gene expression in the two Mdr2-KO strains, we determined a set of regulatory genes that could be responsible for affecting the severity of chronic hepatitis in these strains at an early age. The most prominent was the differential expression of multiple regulators of the NF-κB pathway, which is critical for manifestations of the Mdr2-KO phenotypes.