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.
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L.A.C. is partially supported by R01HL107326 from the National Institutes of Health Heart Lung and Blood Institute (HLBI), for research support cores from P20GM103527 and P30GM127211 from the National Institute of General Medical Sciences, and from the American Heart Association (18SFRB3390001). P.T. was supported through an MMPC from the NIH (U2C DK059630). A.M. was supported for equipment acquisition by NIH 1S100D021753, from NIH HLBI R01 HL120507. M.P. was supported by NIH K99ES028734. A.P.A. was supported by NIH R01 HD076125, R01 DK083561. K.R. was supported by NIH R01 DL083561 and P01 HL028481.
All data are available from the corresponding author upon reasonable request. Raw microarray data (Fig. 4) are available through the Gene Expression Omnibus under the accession code GSE119497. The source data underlying Figs. 1a, 2a-d, 6d, h and 7c and Supplementary Figs. 1a and 5d are provided as a Source Data file.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467- 019-10462-z.
AlSiraj, Yasir; Chen, Xuqi; Thatcher, Sean E.; Temel, Ryan E.; Cai, Lei; Blalock, Eric M.; Katz, Wendy; Ali, Heba M.; Petriello, Michael C.; Deng, Pan; Morris, Andrew J.; Wang, Xuping; Lusis, Aldons J.; Arnold, Arthur P.; Reue, Karen; Thompson, Katherine L.; Tso, Patrick; and Cassis, Lisa A., "XX Sex Chromosome Complement Promotes Atherosclerosis in Mice" (2019). Pharmacology and Nutritional Sciences Faculty Publications. 95.
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