Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice
| Autor: | Alice P. Sowton, Andrew J. Murray, Simon James Tunster, Erica D. Watson, Ben D. McNally, Nisha Padmanabhan, Julian L. Griffin, Antonio Murgia, Aisha Yusuf |
|---|---|
| Přispěvatelé: | Medical Research Council, Medical Research Council (MRC), Sowton, Alice [0000-0002-3718-7783], Tunster, Simon [0000-0002-2242-9452], Murray, Andrew [0000-0002-0929-9315], Watson, Erica [0000-0003-4496-2271], Apollo - University of Cambridge Repository, Watson, Erica D [0000-0003-4496-2271] |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
CE
cholesteryl-ester LC-MS liquid chromatography-mass spectrometry 5-methyl-THF 5-methyltetrahydofolate OXPHOS oxidative phosphorylation G6pc glucose 6-phophastase gene PG phosphatidylglycerol 0601 Biochemistry and Cell Biology Gyg glycogenin gene PIP phosphatidylinositol phosphate(s) Cebpa CCAAT/enhancer binding protein (C/EBP) alpha gene chemistry.chemical_compound Isca1 iron‑sulfur cluster assembly 1 gene PC phosphatidylcholine 0302 clinical medicine Endocrinology Nonalcoholic fatty liver disease One‑carbon metabolism PA phosphatidic acid lcsh:QH301-705.5 0303 health sciences lcsh:R5-920 biology Glycogen FCCP p-trifluoromethoxyphenyl hydrazine 030305 genetics & heredity SAM S-adenosylmethionine Mthfr methylenetetrahydrofolate reductase gene Mtr methionine synthase gene (also MS) PS phosphatidylserine 3. Good health PL phospholipid Gsk3 glycogen synthase kinase gene RIPA Radioimmunoprecipitation assay Agl amylo-alpha-1 6-glucosidase 4-alpha-glucanotransferase gene Ndufs NADH:ubiquinone oxidoreductase core subunit (ETS complex I) gene Liver metabolism Bhmt betaine-homocysteine S-methyltransferase gene Hepatic fuel storage lcsh:Medicine (General) Gbe1 glycogen branching enzyme 1 gene Research Paper medicine.medical_specialty NAFLD non-alcoholic fatty liver disease TAG triacylglycerol NASH non-alcoholic steatohepatitis Cer ceramide PE phosphatidylethanolamine PI phosphatidylinositol 03 medical and health sciences Internal medicine FFA free fatty acid Genetics medicine JO2 oxygen flux Glycogen synthase GSK3A Molecular Biology Myc myelocytomatosis oncogene 0604 Genetics Methionine LPC lysophosphatidylcholine SM sphingomyelin Ddit3 DNA damage inducible transcript 3 gene SAH S-adenosylhomocysteine Lipid metabolism (Methionine synthase) reductase Gys2 glycogen synthase 2 gene Ugp2 UDP-glucose pyrophophorylase 2 gene medicine.disease MTRR HOAD 3-hydoxyacyl-CoA dehydrogenase BCA bicinchoninic acid Mtrr methionine synthase reductase gene (also MSR) chemistry lcsh:Biology (General) gt gene-trap Lipidomics biology.protein Mitochondrial function PAS periodic acid Schiff DAG diacylglycerol 030217 neurology & neurosurgery ETS electron transport system |
| Zdroj: | Molecular Genetics and Metabolism Reports Molecular Genetics and Metabolism Reports, Vol 23, Iss, Pp-(2020) |
| Popis: | Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one‑carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrrgt). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrrgt mutation in mice was previously shown to disrupt one‑carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrrgt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrrgt/gt livers showed evidence of reduced β-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrrgt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrrgt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrrgt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage. Highlights • Mtrrgt is a knockdown mutation in mice that disrupts one-carbon metabolism • Mtrrgt/gt female livers are enlarged, with eosinophilic hepatocytes • Hepatic glycogen content and lipid metabolism is altered in Mtrrgt/gt mice • Mitochondrial electron transfer system activity was unaffected in Mtrrgt/gt livers • Mtrrgt/gt liver phenotype is weaker than other mutations in one-carbon metabolism |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|