XX Sex Chromosome Complement Promotes Atherosclerosis in Mice

Authors

Yasir AlSiraj, University of KentuckyFollow
Xuqi Chen, University of California - Los Angeles
Sean E. Thatcher, University of KentuckyFollow
Ryan E. Temel, University of KentuckyFollow
Lei Cai, University of KentuckyFollow
Eric M. Blalock, University of KentuckyFollow
Wendy Katz, University of KentuckyFollow
Heba M. Ali, University of KentuckyFollow
Michael C. Petriello, University of KentuckyFollow
Pan Deng, University of KentuckyFollow
Andrew J. Morris, University of KentuckyFollow
Xuping Wang, University of California - Los Angeles
Aldons J. Lusis, University of California - Los Angeles
Arthur P. Arnold, University of California - Los Angeles
Karen Reue, University of California - Los Angeles
Katherine L. Thompson, University of KentuckyFollow
Patrick Tso, University of Cincinnati
Lisa A. Cassis, University of KentuckyFollow

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.

Document Type

Article

Publication Date

6-14-2019

Notes/Citation Information

Published in Nature Communications, v. 10, article no. 2631, p. 1-13.

© The Author(s) 2019

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41467-019-10462-z

Funding Information

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.

Related Content

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.

Repository Citation

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.
https://uknowledge.uky.edu/pharmacol_facpub/95