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 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Metabolites - 13(2023), 8 vom: 15. Aug. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Ying [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Animal models |
|---|
| Anmerkungen: |
Date Revised 05.04.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/metabo13080947 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM361221363 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM361221363 | ||
| 003 | DE-627 | ||
| 005 | 20240405233110.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/metabo13080947 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1366.xml |
| 035 | |a (DE-627)NLM361221363 | ||
| 035 | |a (NLM)37623890 | ||
| 035 | |a (PII)947 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 05.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a animal models | |
| 650 | 4 | |a complex diseases | |
| 650 | 4 | |a lipidomics | |
| 650 | 4 | |a mass spectrometry | |
| 650 | 4 | |a physiology | |
| 700 | 1 | |a Barupal, Dinesh K |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Sili |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Flenniken, Ann M |e verfasserin |4 aut | |
| 700 | 1 | |a McKerlie, Colin |e verfasserin |4 aut | |
| 700 | 1 | |a Nutter, Lauryl M J |e verfasserin |4 aut | |
| 700 | 1 | |a Lloyd, Kevin C Kent |e verfasserin |4 aut | |
| 700 | 1 | |a Fiehn, Oliver |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Metabolites |d 2011 |g 13(2023), 8 vom: 15. Aug. |w (DE-627)NLM220344280 |x 2218-1989 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g number:8 |g day:15 |g month:08 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/metabo13080947 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |e 8 |b 15 |c 08 | ||