XX sex chromosome complement promotes atherosclerosis in mice

Yasir AlSiraj; Xuqi Chen; Sean E. Thatcher; Ryan E. Temel; Lei Cai; Eric Blalock; Wendy Katz; Heba M. Ali; Michael Petriello; Pan Deng; Andrew J. Morris; Xuping Wang; Aldons J. Lusis; Arthur P. Arnold; Karen Reue; Katherine Thompson; Patrick Tso; Lisa A. Cassis

doi:10.1038/s41467-019-10462-z

XX sex chromosome complement promotes atherosclerosis in mice

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

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29 Scopus citations

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.

Original language	English
Article number	2631
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10462-z
State	Published - Dec 1 2019

Bibliographical note

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. We acknowledge the medical illustrations provided by Tom Dolan, MS, from the University of Kentucky College of Medicine, for illustrations within Fig. 5F.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

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AlSiraj, Y., Chen, X., Thatcher, S. E., Temel, R. E., Cai, L., Blalock, E., Katz, W., Ali, H. M., Petriello, M., Deng, P., Morris, A. J., Wang, X., Lusis, A. J., Arnold, A. P., Reue, K., Thompson, K., Tso, P., & Cassis, L. A. (2019). XX sex chromosome complement promotes atherosclerosis in mice. Nature Communications, 10(1), [2631]. https://doi.org/10.1038/s41467-019-10462-z

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title = "XX sex chromosome complement promotes atherosclerosis in mice",

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.",

author = "Yasir AlSiraj and Xuqi Chen and Thatcher, {Sean E.} and Temel, {Ryan E.} and Lei Cai and Eric Blalock and Wendy Katz and Ali, {Heba M.} and Michael Petriello and Pan Deng and Morris, {Andrew J.} and Xuping Wang and Lusis, {Aldons J.} and Arnold, {Arthur P.} and Karen Reue and Katherine Thompson and Patrick Tso and Cassis, {Lisa A.}",

note = "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. We acknowledge the medical illustrations provided by Tom Dolan, MS, from the University of Kentucky College of Medicine, for illustrations within Fig. 5F. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - AlSiraj, Yasir

AU - Chen, Xuqi

AU - Thatcher, Sean E.

AU - Temel, Ryan E.

AU - Cai, Lei

AU - Blalock, Eric

AU - Katz, Wendy

AU - Ali, Heba M.

AU - Petriello, Michael

AU - Deng, Pan

AU - Morris, Andrew J.

AU - Wang, Xuping

AU - Lusis, Aldons J.

AU - Arnold, Arthur P.

AU - Reue, Karen

AU - Thompson, Katherine

AU - Tso, Patrick

AU - Cassis, Lisa A.

N1 - 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. We acknowledge the medical illustrations provided by Tom Dolan, MS, from the University of Kentucky College of Medicine, for illustrations within Fig. 5F. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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XX sex chromosome complement promotes atherosclerosis in mice

Abstract

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