The impact of hepatocyte specific Cyp51 disruption on development and sexual dimorphism in mice. Mus musculus

Unperturbed cholesterol homeostasis is important for normal development and sexual maturation in mice. Cyp51 is the rate limiting step in the post-lanosteorl part of cholesterol biosynthesis. Unlike the full body knockout, hepatocyte specific Cyp51 knockout mice survive throughout adulthood, however their livers are severly affected. Several of the hepatocyte specific Cyp51 knockout mice develop severe liver injury or die prior to reaching adulthood (from 4-10 weeks of age; designated as runts). We aim to uncover the timing and the mechanistic background governing the liver damage and sex differences. Hepatocyte-specific Cyp51 knockout and wild type mice on a mixed background (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated at the pre pubertal (3 weeks), late pubertal (6 weeks) and adult (19 weeks) stage of development. This age span allows us to also observe the impact of sexual maturation on the disease development, as the liver is one of the most sexually dimorphic non-reproductive organs. Runt mice were evaluated to differentiate them from the other KO mice with milder conditions. Overall design: 3 factor experimental design: 3 ages (3, 6 and 19 weeks), 2 genotypes (WT, Cyp51 KO), 2 sexes (F, M); 2 biological replicates per condition, 24 mice altogether. Runt mice were also included in the experiment as a separate phenotype (5-7 weeks of age, F and M, Cyp51 KO); 3 biological replicates per sex. A total of 30 microarrays were used.