Project description: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.
Project description:Cholesterol is one of the key molecules in mammals and the most striking examples of its deficiency are the inborn errors of cholesterol biosynthesis that manifest in severe whole body phenotypes. Liver, the principal site of cholesterol homeostasis, has rarely been investigated in these defects. We thus focused on the hepatocyte-specific deletion of lanosterol 14α-demethylase (CYP51) catalyzing the rate-limiting step in the post-squalene part of cholesterol synthesis. Liver-specific Cyp51 KO (LKO or K) and littermate control (LWT or W) mice (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated in the context of different nutritional availability of fat and cholesterol (standard laboratory diet without cholesterol (LFnC or L), high-fat diet without cholesterol (HFnC or H) and high-fat diet with cholesterol (HFC or C) due to the known sexual dimorphism in hepatic gene expression, where lipid metabolic pathways are among the most biased. 3 condition experimental design: 3 diets (LFnC or L, HFnC or H, HFC or C), 2 genotypes (LWT or W, LKO or K), 2 sexes (F, M), 3 biological replicates per condition, 36 mice altogether
Project description:Cholesterol is one of the key molecules in mammals and the most striking examples of its deficiency are the inborn errors of cholesterol biosynthesis that manifest in severe whole body phenotypes. Liver, the principal site of cholesterol homeostasis, has rarely been investigated in these defects. We thus focused on the hepatocyte-specific deletion of lanosterol 14α-demethylase (CYP51) catalyzing the rate-limiting step in the post-squalene part of cholesterol synthesis. Liver-specific Cyp51 KO (LKO or K) and littermate control (LWT or W) mice (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated in the context of different nutritional availability of fat and cholesterol (standard laboratory diet without cholesterol (LFnC or L), high-fat diet without cholesterol (HFnC or H) and high-fat diet with cholesterol (HFC or C) due to the known sexual dimorphism in hepatic gene expression, where lipid metabolic pathways are among the most biased.
Project description:The potential role of defective cholesterol metabolism in HCC development and exposition the Cyp51 gene as a promising marker with tumor suppressor potential in sex-dimorphic chronic liver pathogenesis in mice. Hepatocyte-specific Cyp51 knock-out (KO) and wild type (WT) mice on a mixed background (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated at the age of 24 months. From each of KO mice, two samples (a tumor and a surrounding tissue) were considered.
Project description:The impact of defective cholesterol metabolism on sex-specific hepatocarcinogenesis in hepatocyte specific deletion of Cyp51 in mice
Project description:Hepatic gene expression shows sexual dimorphism. Here, we investigated the role of BCL6 in establishing sexual dimorphism in hepatic gene expression and created Bcl6Flox/Flox,Alb-Cre mice and performed RNAseq from livers of 4- and 8-week-old male and female Ctrl and BCL6 liver knock-out mice.
Project description:Sexual dimorphisms are well recognized in various cardiac diseases, including myocardial infarction (MI). MI develops later in women, but once established, it contributes more persistent symptoms and higher mortality than in men. Similar observations have been reported in murine model of MI. Although mRNA-level sexual dimorphism of MI have been reported, whether miRNA transcriptome also confers such dimorphism remains unknown. Comprehensive understanding of the mRNA- and miRNA-level genetic programs underlying the heart sexual dimorphisms will expectedly improve clinical outcome by facilitating the development of gender specific treatment strategies. Here, by conducting miRNA microarray analysis of murine MI model samples, we set out to characterize the heart sexual dimorphisms at the level of miRNA transcriptome The left anterior descending (LAD) coronary artery of mice aged 10 weeks was surgically ligated to create extensive MI. The ventricular septum of the areas at risk of ischemia was sampled on post-operative day 28. Total RNA was extracted using Sepasol solution (Sepasol-RNA I super G, nakalai tesque, Japan), and microarray analysis was performed using Affymetrix GeneChip® miRNA 3.0 Arrays
