Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice
| Autor: | Martines, Anne-Claire M F, Gerding, Albert, Stolle, Sarah, Vieira-Lara, Marcel A, Wolters, Justina C, Jurdzinski, Angelika, Bongiovanni, Laura, de Bruin, Alain, van der Vlies, Pieter, van der Vries, Gerben, Bloks, Vincent W, Derks, Terry G J, Reijngoud, Dirk-Jan, Bakker, Barbara M, LS Pathobiologie, dPB RMSC |
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| Přispěvatelé: | LS Pathobiologie, dPB RMSC, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Coenzyme A lcsh:Medicine Dehydrogenase Isozyme Cofactor Transcriptome 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine lcsh:Science chemistry.chemical_classification Multidisciplinary biology lcsh:R nutritional and metabolic diseases 030104 developmental biology Endocrinology Enzyme chemistry Knockout mouse biology.protein lcsh:Q NAD+ kinase 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports, 9(1). NLM (Medline) Scientific Reports, 9(1):14539. Nature Publishing Group |
| ISSN: | 2045-2322 |
| Popis: | During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity. |
| Databáze: | OpenAIRE |
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