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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