Abstract
Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.
Highlights
Men and women differ in circulating lipids and coronary artery disease (CAD)
Our results demonstrate that an XX sex chromosome genotype, relative to XY, promotes the development of atherosclerotic lesions in multiple mouse models and this is associated with profound dyslipidemia, enhanced adiposity, and augmented dietary fat bioavailability
We demonstrate that relative to XY, mice with an XX sex chromosome genotype exhibit the following: (1) markedly elevated serum cholesterol and TG concentrations, effects that were found in different experimental paradigms, (2) profound elevations in atherosclerosis, (3) altered expression of hepatic genes associated with immune pathways, (4) similar hepatic TG secretion but higher levels of newly synthesized apolipoprotein B100, (5) greater expression levels of key genes in small intestine involved in lipid absorption and chylomicron assembly, higher intestinal lipid content, and modest elevations in % fat absorption (Fig. 5f)
Summary
Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. A plethora of research has focused on the role of sex hormones as mediators of sex differences in a variety of diseases, most especially cardiovascular diseases[1,2] Results from these studies suggest that estrogens have beneficial effects on circulating lipid profiles (e.g., increase HDL)[3,4,5,6] and protect against coronary artery disease (CAD)[7,8,9,10], and that these benefits are typically lost in postmenopausal females. Some studies report that postmenopausal females exhibit a pro-atherogenic lipid profile and an increase in CAD to a level that catches up to, but exceeds that of age-matched males[11,12,13] This suggests that female gonadal hormones, such as estrogens, are unlikely to be the only determinant of sex differences in CAD risk. Our findings may have important ramifications for human health, following menopause, when protective effects of female sex hormones are lost, and the effects of an XX sex chromosome genotype may contribute to pro-atherogenic lipid profiles and CAD
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