Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes - PubMed (original) (raw)

Comparative Study

Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes

Jenny C Link et al. Arterioscler Thromb Vasc Biol. 2015 Aug.

Abstract

Objective: The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels.

Approach and results: We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male-female gonadal sex and XX-XY chromosome complement. Gonadectomy of adult mice revealed that the male-female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male-female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration.

Conclusions: We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels.

Keywords: HDL cholesterol; diet; female; male; mice.

PubMed Disclaimer

Figures

Figure 1

Plasma lipid levels are regulated by both gonadal sex and sex chromosome complement. A and B, Concentrations of total cholesterol (TC), unesterified cholesterol (UC), high-density lipoprotein (HDL) cholesterol, triglycerides (TG), and free fatty acids (FFA) were measured in 7.5-month-old gonadally intact (A) and gonadectomized (GDX, B) Four Core Genotypes mice fed a standard chow diet (n = 8). Low-density lipoprotein (LDL) cholesterol values were calculated by subtracting HDL from TC. Values represent the mean ± standard deviation. Significant comparisons for sex chromosome complement and for gonadal sex are denoted by brackets. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Int.” *, _P_≤0.05; **, _P_≤0.01; ***,_P_≤0.001; ‡, _P_≤0.000001. F, gonadal female; M, gonadal male.

Figure 2

HDL lipoprotein composition and apoAI exchange activity is influenced by sex. Plasma was collected from 7.5-month-old gonadally intact (A, D) and gonadectomized (GDX, B, E) chow-fed mice. A and B, Three representative plasma samples from each genotype were pooled and assayed using fast protein liquid chromatography. C, Plasma levels of apolipoproteins were quantified by immunoblot densitometry. Direction of statistically significant comparisons for gonadal sex and for sex chromosomes are shown. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Interaction.” D and E, HDL apoAI dissociation activity was measured by electron paramagnetic resonance and represented as % response. Values represent the mean ± standard deviation. *, _P_≤0.05; **, _P_≤0.01; ***,_P_≤0.001; n.s., not significant. F, gonadal female; M, gonadal male.

Figure 3

Diet interacts with gonadal sex and sex chromosome complement to modulate plasma lipid levels. A and B, Concentrations of total cholesterol (TC), unesterified cholesterol (UC), high-density lipoprotein (HDL) cholesterol, triglycerides (TG), and free fatty acids (FFA) were determined in 7.5-month-old gonadally intact (A) and GDX (B) FCG mice fed a high cholesterol diet (HCD, n = 4-10). Low-density lipoprotein (LDL) cholesterol values were calculated by subtracting HDL from TC. Values represent the mean ± standard deviation. Significant comparisons for sex chromosome complement and for gonadal sex are denoted by brackets. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Int.” *, _P_≤0.05; **, _P_≤0.01; ***,_P_≤0.001; †, _P_≤0.0001. F, gonadal female; M, gonadal male.

Figure 4

Diet interacts with sex to influence HDL lipoprotein composition and apoAI exchange activity. Plasma was collected from 7.5-month-old gonadally intact (A, D) and gonadectomized (GDX, B, E) mice fed the high cholesterol diet (HCD). A and B, Three representative plasma samples from each genotype were pooled and assayed using fast protein liquid chromatography. C, Plasma levels of apolipoproteins were quantified by immunoblot densitometry. Direction of statistically significant comparisons for gonadal sex and for sex chromosomes are shown. A significant interaction of sex chromosome complement and gonadal sex is denoted by “Interaction.” D and E, HDL apoAI dissociation activity was measured by electron paramagnetic resonance and represented as % response and as activity per unit of HDL cholesterol. Values represent the mean ± standard deviation. *, _P_≤0.05; **, _P_≤0.01; †, _P_≤0.0001; n.s., not significant. F, gonadal female; M, gonadal male.

Figure 5

Elevated total and HDL cholesterol levels are associated with presence of two X chromosomes. Concentrations of total cholesterol (TC), unesterified cholesterol (UC), high-density lipoprotein (HDL) cholesterol, triglyceride (TG), and free fatty acids (FFA) were measured in gonadectomized XY* chow fed mice with the sex chromosome genotypes indicated (n = 7-8). Low-density lipoprotein (LDL) cholesterol values were calculated by subtracting HDL from TC. Values represent the mean ± standard deviation. Significant comparisons by one-way ANOVA with Duncan's multiple-comparison test are denoted by brackets. *, _P_≤0.05; **, _P_≤0.01.

Figure 6

Factors influencing circulating HDL cholesterol. A, HDL cholesterol levels are higher in XX mice compared to XY mice, regardless of diet or sex hormone presence status. Male/female gonad status also influences HDL cholesterol levels under some conditions. B, Plasma lipid other than HDL exhibit sex differences that depend on the diet and gonadal status. High cholesterol diet (HCD); gonadectomy (GDX); F, gonadal female; M, gonadal male. C, Mice with two X chromosomes have increased X escapee gene expression in metabolic tissues such as liver. These genes may influence several metabolic pathways to increase circulating HDL cholesterol.

References

1. Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, Warnes GR, Gómez Pérez FJ, Frazer KA, Elliott P, Scott J, Milos PM, Cox DR, Thompson JF. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008;40:149–151. - PubMed
1. Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65. - PMC - PubMed
1. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–713. - PMC - PubMed
1. Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–1283. - PMC - PubMed
1. Freedman DS, Otvos JD, Jeyarajah EJ, Shalaurova I, Cupples LA, Parise H, D'Agostino RB, Wilson PWF, Schaefer EJ. Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: the Framingham Study. Clin Chem. 2004;50:1189–1200. - PubMed

Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes - PubMed (original) (raw)