University of Groningen
Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine
Martines, Anne-Claire
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Martines, A-C. (2019). Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Exploring the mechanisms underlying
the phenotype of MCAD deficiency
with Systems Medicine
From computational model to mice to man
The work described in this thesis was carried out at the department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, the Netherlands. The research described in this thesis was funded by the University Medical Center Groningen. The research group participates in the Groningen Institute for Drug Exploration (GUIDE).
The author gratefully acknowledges the financial support for printing this thesis by: Avanti Polar Lipids, Inc. (www.avantilipids.com).
Groningen Institute for Drug Exploration (GUIDE). Rijksuniversiteit Groningen (RuG)
University Medical Center Groningen (UMCG) Thuis Ontzorgt (www.thuisontzorgt.nl) Favorability B.V.
Bert Middelwijk Joop Tertaas
Cover design: Studio JNNFR
Cover meaning: The cover is in honor of all who contribute passionately to gain more insight into MCAD deficiency to help all MCAD-deficient individuals live a fuller life.
Protein and metabolite images on the back cover are from Pubchem (NAD+ and
acyl-carnitines), WikiCommons (Coenzyme A) and RCSB PDB (K304E-mutant MCAD (PDB ID: 4P13) and SCAD (PDB ID: 2VIG), both generated with NGL viewer (PMID: 29850778)) Layout: Anne-Claire M.F. Martines
Printed by: Ridderprint BV, Ridderkerk, The Netherlands ISBN:
978-94-034-1799-8 (Printed version) 978-94-034-1798-1 (Digital version) © A.M.F. Martines, 2019
All rights reserved. No part of this thesis may be reproduced, distributed stored in a retrieval system, or transmitted in any form or by any means without prior permission of the author, or where applicable, the publisher holding the copyright on the published articles.
Exploring the mechanisms
underlying the phenotype of MCAD
deficiency with Systems Medicine
From computational model to mice to man
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op
woensdag 10 juli 2019 om 16.15 uur
door
Anne-Claire Micheline Francisca Martines
geboren op 10 oktober 1981 te Willemstad, Curaçao
Promotores
Prof. dr. B.M. Bakker Prof. dr. D.J. Reijngoud
Beoordelingscommissie
Prof. dr. F.J. Bruggeman Prof. dr. A.K. Groen Prof. dr. F.J. van Spronsen
This PhD thesis is dedicated to my lovely parents,
Ingrid Martines-Kirindongo and Edwin Martines,
and my loving husband, Amart Schoop, who have
always supported me through thick and thin
Paranimfen
Natasha Tearr-Marcos Aduni Mariana
CONTENTS
Chapter 1 General introduction and outline of the thesis 9
Chapter 2 The promiscuous enzyme medium-chain 3-keto-acyl-CoA
thiolase triggers a vicious cycle in fatty-acid beta-oxidation 39
Chapter 3 Transcriptomic analysis suggests a compensatory role of
cofactors coenzyme A and NAD+ in medium-chain acyl-CoA
dehydrogenase knockout mice
67
Chapter 4 The role of hepatic fatty-acid oxidation during cold stress:
remodeling of hepatic metabolism in a mouse with medium-chain acyl-CoA dehydrogenase deficiency
127
Chapter 5 Simulating the impact of genetic and environmental
modifiers on MCAD deficiency in an extended model of human liver fatty-acid catabolism
157
Chapter 6 Towards identifying in vitro metabolic adaptations that
explain symptomatology in MCADD individuals. A short report
205
Chapter 7 General discussion 225
Appendix 241 Summary 243 Samenvatting 249 Acknowledgements 255 Biography 265 Portfolio 269 List of publications 273
