Fig. 1.

Study design using hypercholesterolemic Four Core Genotypes mice, and sex determinants of plasma lipid level response to statin. A Experimental design to assess the contribution of sex components to lipid levels and hepatic transcriptome. Left, generation of FCG mouse cohorts on hypercholesterolemic (Apoe^–/–) genetic background. Center, group comparisons made throughout the study. Right, a summary of analyses performed. B Total cholesterol levels, C triglyceride levels, D and free fatty acid levels in plasma of Apoe^–/– FCG mice on chow diet (left panel, N = 3–6/genotype), treated with simvastatin (center panel, N = 4–7/genotype) represented as mean ± standard deviation. The right graph in panels B–D depicts the statin-induced change in lipid levels relative to levels on chow diet (horizontal dashed line). The statin-induced lipid changes were calculated as the difference between the mean lipid level for each genotype without statin treatment and the lipid level of each individual mouse after statin treatment; box plots show the minimum, median, and maximum values for statin-induced lipid changes. All data shown in panels B–D were analyzed by two-way ANOVA for gonad and sex chromosome type, and significant differences are indicated by brackets. In two-way ANOVA analyses, two groups of mice were combined (such as XX plus XY mice with ovaries, or XX plus XY mice with testes) such that the number of mice in each group used for statistical analysis is 7–12. * indicates gonadal sex effect, † indicates chromosomal sex effect, int. indicates interaction between gonadal and chromosomal sex. Denoted significance values: *P < 0.05, ** or ^††P < 0.01, ***P < 0.001, ****P < 0.0001