Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.
Adenosine Triphosphate
/ metabolism
Animals
Disease Models, Animal
Female
Humans
Leucovorin
/ analogs & derivatives
Lipid Metabolism
/ genetics
Male
Metabolomics
/ methods
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ metabolism
NADP
/ metabolism
Oxidoreductases Acting on CH-NH Group Donors
/ deficiency
Sjogren-Larsson Syndrome
/ genetics
Tetrahydrofolates
/ metabolism
ALDH1L2
Coenzyme A
Folate metabolism
Knockout mouse model
Metabolomics
NADPH
Oxidative stress
β-oxidation
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
09 11 2020
09 11 2020
Historique:
received:
21
09
2020
accepted:
14
10
2020
entrez:
10
11
2020
pubmed:
11
11
2020
medline:
21
10
2021
Statut:
epublish
Résumé
Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2 The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.
Sections du résumé
BACKGROUND
Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO
METHODS
We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways.
RESULTS
Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2
CONCLUSIONS
The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.
Identifiants
pubmed: 33168096
doi: 10.1186/s40246-020-00291-3
pii: 10.1186/s40246-020-00291-3
pmc: PMC7654619
doi:
Substances chimiques
Tetrahydrofolates
0
10-formyltetrahydropteroylglutamic acid
2800-34-2
5,6,7,8-tetrahydrofolic acid
43ZWB253H4
NADP
53-59-8
Adenosine Triphosphate
8L70Q75FXE
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
formyltetrahydrofolate dehydrogenase
EC 1.5.1.6
Leucovorin
Q573I9DVLP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
41Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK117854
Pays : United States
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