Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice

Abstract:

Abstract 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.

SEEK ID: https://fairdomhub.org/publications/461

DOI: 10.1038/s41598-019-50758-0

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Publication type: Journal

Journal: Scientific Reports

Citation: Sci Rep 9(1)

Date Published: 1st Dec 2019

Registered Mode: by DOI

Authors: Anne-Claire M. F. Martines, Albert Gerding, Sarah Stolle, Marcel A. Vieira-Lara, Justina C. Wolters, Angelika Jurdzinski, Laura Bongiovanni, Alain de Bruin, Pieter van der Vlies, Gerben van der Vries, Vincent W. Bloks, Terry G. J. Derks, Dirk-Jan Reijngoud, Barbara M. Bakker

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Martines, A.-C. M. F., Gerding, A., Stolle, S., Vieira-Lara, M. A., Wolters, J. C., Jurdzinski, A., Bongiovanni, L., de Bruin, A., van der Vlies, P., van der Vries, G., Bloks, V. W., Derks, T. G. J., Reijngoud, D.-J., & Bakker, B. M. (2019). Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice. In Scientific Reports (Vol. 9, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41598-019-50758-0
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Created: 2nd Apr 2020 at 16:57

Last updated: 2nd Apr 2020 at 16:58

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