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

ABSTRACT: 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.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.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.

SUBMITTER: Link JC

PROVIDER: S-EPMC4668127 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Link Jenny C JC Chen Xuqi X Prien Christopher C Borja Mark S MS Hammerson Bradley B Oda Michael N MN Arnold Arthur P AP Reue Karen K

Arteriosclerosis, thrombosis, and vascular biology 20150625 8

<h4>Objective</h4>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.<h4>Approach and results</h4>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-f ...[more]

PMID: 26112012

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Project description:Background Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex-specific differential effect of genetically increased low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) and other lipid-associated diseases. Methods and Results This is a 2-sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80-variant LDL-C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex-specific LDL-C effects on lipids, carotid-intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL-C effect on CVD events was sex specific: per SD genetically increased LDL-C, female participants had a higher LDL-C increase but an attenuated CVD risk increase compared with male participants (LDL-C: female participants 0.71 mmol/L, 95% CI, 0.70-0.72 and male participants 0.57 mmol/L, 95% CI, 0.56-0.59. P for interaction: 5.03×10-60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24-1.40 and male participants: OR, 1.52; 95% CI, 1.46-1.58. P for interaction: 9.88×10-5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL-C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL-C was also associated with an attenuated carotid-intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex-specific weighted genetic scores showed similar results. Conclusions We found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL-C targeted therapies for CVD management than female patients and warranting investigations into the sex-specific relative contribution of risk factors for CVD.

Dataset Information

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

Publications

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

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