title: Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Link
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Xuqi
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Prien
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Mark S
authors.initials: MS
authors.lastname: Borja
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Bradley
authors.initials: B
authors.lastname: Hammerson
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.).
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Arnold
authors.affiliation: From the Molecular Biology Institute (J.C.L., K.R.), Department of Integrative Biology and Physiology (X.C., A.P.A.), Laboratory of Neuroendocrinology of the Brain Research Institute (X.C., A.P.A.), Department of Human Genetics, David Geffen School of Medicine (C.P., K.R.), and Department of Medicine, David Geffen School of Medicine (K.R.), University of California, Los Angeles; and Children's Hospital Oakland Research Institute, California (M.S.B., B.H., M.N.O.). reuek@ucla.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood* / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism; D010641:Phenotype; D012727:Sex Characteristics; D012737:Sex Factors; D013737:Testis / Q000378:metabolism; D015854:Up-Regulation; D014960:X Chromosome; D014998:Y Chromosome
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D012739:Gonadal Steroid Hormones
keywords: HDL cholesterol; diet; female; male; mice