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

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 investigate...

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Autores principales: Zhang, Ying, Barupal, Dinesh K., Fan, Sili, Gao, Bei, Zhu, Chao, Flenniken, Ann M., McKerlie, Colin, Nutter, Lauryl M. J., Lloyd, Kevin C. Kent, Fiehn, Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10456929/
https://www.ncbi.nlm.nih.gov/pubmed/37623890
http://dx.doi.org/10.3390/metabo13080947
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author Zhang, Ying
Barupal, Dinesh K.
Fan, Sili
Gao, Bei
Zhu, Chao
Flenniken, Ann M.
McKerlie, Colin
Nutter, Lauryl M. J.
Lloyd, Kevin C. Kent
Fiehn, Oliver
author_facet Zhang, Ying
Barupal, Dinesh K.
Fan, Sili
Gao, Bei
Zhu, Chao
Flenniken, Ann M.
McKerlie, Colin
Nutter, Lauryl M. J.
Lloyd, Kevin C. Kent
Fiehn, Oliver
author_sort Zhang, Ying
collection PubMed
description 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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spelling pubmed-104569292023-08-26 Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines Zhang, Ying Barupal, Dinesh K. Fan, Sili Gao, Bei Zhu, Chao Flenniken, Ann M. McKerlie, Colin Nutter, Lauryl M. J. Lloyd, Kevin C. Kent Fiehn, Oliver Metabolites Article 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. MDPI 2023-08-15 /pmc/articles/PMC10456929/ /pubmed/37623890 http://dx.doi.org/10.3390/metabo13080947 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Ying
Barupal, Dinesh K.
Fan, Sili
Gao, Bei
Zhu, Chao
Flenniken, Ann M.
McKerlie, Colin
Nutter, Lauryl M. J.
Lloyd, Kevin C. Kent
Fiehn, Oliver
Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title_full Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title_fullStr Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title_full_unstemmed Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title_short Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines
title_sort sexual dimorphism of the mouse plasma metabolome is associated with phenotypes of 30 gene knockout lines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10456929/
https://www.ncbi.nlm.nih.gov/pubmed/37623890
http://dx.doi.org/10.3390/metabo13080947
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