University of Groningen Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis Grefhorst, Aldo 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: 2006 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Grefhorst, A. (2006). Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis s.n. 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. Download date: 05-01-2019
Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis
Copyright 2005 A. Grefhorst All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means without written permission of the author and the publisher holding the copyright of the published articles. Cover and page design: Maaike Leemreize and Aldo Grefhorst Printed by Ponsen & Looijen B.V., Wageningen, The Netherlands
RIJKSUNIVERSITEIT GRONINGEN Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 18 januari 2006 om 16.15 uur door Aldo Grefhorst geboren op 25 oktober 1974 te Apeldoorn
Promotores Prof. dr. F. Kuipers Prof. dr. L.M. Havekes Prof. dr. J.A. Romijn Beoordelingscommissie Prof. dr. J.D. Horton Prof. dr. P.J.J. Sauer Prof. dr. B. Staels ISBN papieren versie: 90-367-2469-4 ISBN elektronische versie: 90-367-2470-8
Paranimfen Arnout van der Borden Ronald Grefhorst Research The studies described in this thesis were conducted within the Groningen University Institute for Drug Exploration (GUIDE), Center for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands. Funding The studies described in this thesis were supported by grant 903-39-291 from the Netherlands Organization for Scientific Research (NWO), Den Haag, The Netherlands. Printing of this thesis was financially supported by Diabetesfonds Nederland, Amersfoort, The Netherlands Rijksuniversiteit Groningen, Groningen, The Netherlands Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands Nederlandse Vereniging voor Hepatologie, Haarlem, The Netherlands Harlan Nederland, Horst, The Netherlands Their contribution is gratefully acknowledged!
Table of contents Chapter 1 General introduction 9 Chapter 2 Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice 29 Chapter 3 Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles 47 Chapter 4 Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice 69 Chapter 5 Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity: a novel therapeutic approach to insulin resistance 87 Chapter 6 Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very low density lipoprotein production 103 Chapter 7 Induction of hepatic lipogenic gene expression upon pharmacological inhibition of glucose-6-phosphate translocase is independent of liver X receptor alpha 119 Chapter 8 The role of lipogenic transcription factors in diabetic dyslipidemia 133 Chapter 9 Summary and general discussion 151 Nederlandse samenvatting 161 Dankwoord Curriculum vitae List of publications Colour figures