Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder
| Autor: | Susan Sumner, Natalia I. Krupenko, Kristi L. Helke, Sergey A. Krupenko, Madeline S. Hall, Jaspreet Sharma, Peter Pediaditakis, Xiuxia Du |
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| Rok vydání: | 2020 |
| Předmět: |
Male
lcsh:QH426-470 Coenzyme A Leucovorin lcsh:Medicine ALDH1L2 Mitochondrion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Adenosine Triphosphate Lipid oxidation Drug Discovery Genetics NADPH Animals Humans Metabolomics Molecular Biology Tetrahydrofolates 030304 developmental biology chemistry.chemical_classification Mice Knockout 0303 health sciences Oxidoreductases Acting on CH-NH Group Donors lcsh:R Lipid metabolism Glutathione Folate metabolism Lipid Metabolism Mitochondria Citric acid cycle Mice Inbred C57BL lcsh:Genetics Disease Models Animal Sjogren-Larsson Syndrome Enzyme Knockout mouse model chemistry Biochemistry Oxidative stress 030220 oncology & carcinogenesis Knockout mouse Molecular Medicine β-oxidation Female Primary Research NADP |
| Zdroj: | Human Genomics Human Genomics, Vol 14, Iss 1, Pp 1-15 (2020) |
| ISSN: | 1479-7364 |
| Popis: | Background Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. 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-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. 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. |
| Databáze: | OpenAIRE |
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