Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines

被引:3
作者
Zhang, Ying [1 ,2 ]
Barupal, Dinesh K. [3 ]
Fan, Sili [1 ]
Gao, Bei [4 ]
Zhu, Chao [5 ]
Flenniken, Ann M. [6 ,7 ]
Mckerlie, Colin [6 ,8 ]
Nutter, Lauryl M. J. [6 ,8 ]
Lloyd, Kevin C. Kent [9 ,10 ]
Fiehn, Oliver [1 ]
机构
[1] Univ Calif Davis, West Coast Metabol Ctr, Davis, CA 95616 USA
[2] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA
[3] Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY 10029 USA
[4] Nanjing Univ Informat Sci & Technol, Sch Marine Sci, Nanjing 210044, Peoples R China
[5] Dezhou Univ, Coll Med & Nursing, Dezhou 253023, Peoples R China
[6] Ctr Phenogen, Toronto, ON M5T 3H7, Canada
[7] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada
[8] Hosp Sick Children, Toronto, ON M5G 1X8, Canada
[9] Univ Calif Davis, Sch Med, Dept Surg, Davis, CA 95616 USA
[10] Univ Calif Davis, Mouse Biol Program, Davis, CA 95616 USA
关键词
animal models; lipidomics; mass spectrometry; physiology; complex diseases; TRIMETHYLAMINE-N-OXIDE; RECEPTOR RNA ACTIVATOR; ANIMAL-MODELS; HORMONAL-CONTROL; BLOOD-PRESSURE; CANCER RISK; PROTEIN; DISEASE; CELL; EXPRESSION;
D O I
10.3390/metabo13080947
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although metabolic alterations are observed in many monogenic and complex genetic disorders, the impact of most mammalian genes on cellular metabolism remains unknown. Understanding the effect of mouse gene dysfunction on metabolism can inform the functions of their human orthologues. We investigated the effect of loss-of-function mutations in 30 unique gene knockout (KO) lines on plasma metabolites, including genes coding for structural proteins (11 of 30), metabolic pathway enzymes (12 of 30) and protein kinases (7 of 30). Steroids, bile acids, oxylipins, primary metabolites, biogenic amines and complex lipids were analyzed with dedicated mass spectrometry platforms, yielding 827 identified metabolites in male and female KO mice and wildtype (WT) controls. Twenty-two percent of 23,698 KO versus WT comparison tests showed significant genotype effects on plasma metabolites. Fifty-six percent of identified metabolites were significantly different between the sexes in WT mice. Many of these metabolites were also found to have sexually dimorphic changes in KO lines. We used plasma metabolites to complement phenotype information exemplified for Dhfr, Idh1, Mfap4, Nek2, Npc2, Phyh and Sra1. The association of plasma metabolites with IMPC phenotypes showed dramatic sexual dimorphism in wildtype mice. We demonstrate how to link metabolomics to genotypes and (disease) phenotypes. Sex must be considered as critical factor in the biological interpretation of gene functions.
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页数:25
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共 115 条
  • [11] A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD
    Brandsma, Corry-Anke
    van den Berge, Maarten
    Postma, Dirkje S.
    Jonker, Marnix R.
    Brouwer, Sharon
    Pare, Peter D.
    Sin, Don D.
    Bosse, Yohan
    Laviolette, Michel
    Karjalainen, Juha
    Fehrmann, Rudolf S. N.
    Nickle, David C.
    Hao, Ke
    Spanjer, Anita I. R.
    Timens, Wim
    Franke, Lude
    [J]. THORAX, 2015, 70 (01) : 21 - 32
  • [12] Toward Merging Untargeted and Targeted Methods in Mass Spectrometry-Based Metabolomics and Lipidomics
    Cajka, Tomas
    Fiehn, Oliver
    [J]. ANALYTICAL CHEMISTRY, 2016, 88 (01) : 524 - 545
  • [13] Dietary modulation of oxylipins in cardiovascular disease and aging
    Caligiuri, Stephanie P. B.
    Parikh, Mihir
    Stamenkovic, Aleksandra
    Pierce, Grant N.
    Aukema, Harold M.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2017, 313 (05): : H903 - H918
  • [14] Dietary Flaxseed Reduces Central Aortic Blood Pressure Without Cardiac Involvement but Through Changes in Plasma Oxylipins
    Caligiuri, Stephanie P. B.
    Rodriguez-Leyva, Delfin
    Aukema, Harold M.
    Ravandi, Amir
    Weighell, Wendy
    Guzman, Randolph
    Pierce, Grant N.
    [J]. HYPERTENSION, 2016, 68 (04) : 1031 - 1038
  • [15] Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer
    Camarda, Roman
    Zhou, Alicia Y.
    Kohnz, Rebecca A.
    Balakrishnan, Sanjeev
    Mahieu, Celine
    Anderton, Brittany
    Eyob, Henok
    Kajimura, Shingo
    Tward, Aaron
    Krings, Gregor
    Nomura, Daniel K.
    Goga, Andrei
    [J]. NATURE MEDICINE, 2016, 22 (04) : 427 - +
  • [16] Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?
    Cho, Clara E.
    Caudill, Marie A.
    [J]. TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2017, 28 (02) : 121 - 130
  • [17] Reversed phase UHPLC/ESI-MS determination of oxylipins in human plasma: a case study of female breast cancer
    Chocholouskova, Michaela
    Jirasko, Robert
    Vrana, David
    Gatek, Jiri
    Melichar, Bohuslav
    Holcapek, Michal
    [J]. ANALYTICAL AND BIOANALYTICAL CHEMISTRY, 2019, 411 (06) : 1239 - 1251
  • [18] NIH to balance sex in cell and animal studies
    Clayton, Janine A.
    Collins, Francis S.
    [J]. NATURE, 2014, 509 (7500) : 282 - 283
  • [19] The hormonal control of food intake
    Coll, Anthony P.
    Farooqi, I. Sadaf
    O'Rahilly, Stephen
    [J]. CELL, 2007, 129 (02) : 251 - 262
  • [20] Steroid Receptor RNA Activator - A nuclear receptor coregulator with multiple partners: Insights and challenges
    Colley, Shane M.
    Leedman, Peter J.
    [J]. BIOCHIMIE, 2011, 93 (11) : 1966 - 1972