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University of Groningen New Insights Into the Biological Role of COMMD1 University of Groningen New insights into the biological role of COMMD1 Bartuzi, Paulina 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: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Bartuzi, P. (2014). New insights into the biological role of COMMD1: from inflammation to steatosis and hypercholesterolemia. [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). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. 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: 06-10-2021 New insights into the biological role of COMMD1 From inflammation to steatosis and hypercholesterolemia Paulina Anna Bartuzi ISBN: 978-90-367-7405-5 ISBN (ebook): 978-90-367-7404-8 Funding The research described in this thesis was supported by Groningen University Institute for Drug Exploration (GUIDE) and Jan Kornelis de Cock Stichting. Printing of this thesis was financially supported by University of Groningen, Groningen, the Netherlands; University Medical Center Groningen (UMCG), Groningen, the Netherlands; Groningen University Institute for Drug Exploration (GUIDE), Groningen, the Netherlands Nederlandse Vereniging voor Hepatologie (NVH) ©2014, Paulina Bartuzi No part of this book may be reproduced, stored in 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. Cover design: Paulina Bartuzi Book layout: Lovebird design & printing solutions (www.lovebird-design.com) Printed by: EIKON Plus, Kraków, Poland ISBN: 978-90-367-7405-5 ISBN (ebook): 978-90-367-7404-8 New insights into the biological role of COMMD1 From inflammation to steatosis and hypercholesterolemia PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on Wednesday 10 December 2014 at 09.00 hours by Paulina Anna Bartuzi born on 1 August 1986 in Kraków, Poland Supervisor Prof. M.H. Hofker Co-supervisor Dr. ing A.J.A. van de Sluis Assessment committee Prof. K. Willems van Dijk Prof. K.N. Faber Prof. M.P.J. de Winther CONTENTS PREFACE 7 CHAPTER 1 General introduction 9 CHAPTER 2 Tuning NF-κB: A touch of COMMD proteins 25 CHAPTER 3 Functional understanding of the versatile protein 43 copper metabolism MURR1 domain 1 (COMMD1) in copper homeostasis CHAPTER 4 Copper metabolism domain containing 1 represses genes 59 that promote inflammation and protects mice from colitis and colitis-associated cancer CHAPTER 5 A cell-type-specific role for Commd1 in liver inflammation 91 CHAPTER 6 Loss of hepatocyte COMMD1 results in increased levels 113 of circulating low-density lipoprotein cholesterol CHAPTER 7 Hepatic COMMD1 deficiency is associated with liver 135 microsteatosis and decreased inflammation upon long-term high-fat, high cholesterol feeding CHAPTER 8 Discussion 151 SUMMARIES Summary 171 Podsumowanie 173 Samenvatting 176 Acknowledgements 179 Curriculum Vitae 181 List of publications 182 PREFACE Our current knowledge of the COMMD family originates mainly from studies on COMMD1, but there is still a lot to learn about the mechanisms and cell-type specific differences governing the function of COMMD1. To date, all the information available on the role of Commd1 in biological pathways other than copper metabolism has come solely from in vitro cell experiments. The studies described in this thesis aim to investigate the role of Commd1 during hepatic steatosis and inflammation in vivo, using conditional Commd1- deficient mice. This thesis gives new insights into the possible functions of COMMD1, as the loss of Commd1 affects hepatic lipid accumulation, clearance of circulating LDL-c, and NF-κB regulation. The thesis consists of eight chapters. Chapter 1 briefly introduces the topic and pathogenesis of non-alcoholic fatty liver disease (NAFLD). It also summarizes low- density lipoprotein (LDL) trafficking through LDL receptor (LDLR) and introduces the aspect of multifunctionality of COMMD1. Chapter 2 provides an overview of the actions of COMMD family with respect to NF-κB pathway. Nevertheless, the main focus of this chapter is COMMD1 as the prototype of the family. In Chapter 3 the role of COMMD1 in vesicular transport, especially its interaction and regulation of hepatic copper export through P-type ATPase transporters Atp7A and Atp7B is described. Chapter 4 provides the first in vivo proof of COMMD1’s role in suppressing the inflammatory response. A mouse model of a conditional myeloid-specific Commd1 knockout (Commd1∆Mye) is described in the context of colitis and sepsis. Further clarification of the role of COMMD1 in hepatocytes is presented in Chapter 5. The focus of this chapter is to dissect cell-type-specific differences in the function of Commd1 in the liver during non-alcoholic fatty liver disease (NAFLD). Two conditional knockouts placed on a high-fat, high-cholesterol (HFC) diet for 12 weeks were investigated: hepatocyte (Commd1∆Hep) and myeloid-specific (Commd1∆Mye). Chapter 5 provides a novel role for Commd1 in steatosis progression and advocates that it has no evident action on hepatic inflammation. On the contrary, myeloid Commd1 suppresses liver inflammation during the progression of NAFLD to NASH. Following on from the role of dyslipidemia feature of NAFLD, Chapter 6 presents a novel link between Commd1 and hypercholesterolemia. Commd1∆Hep mice were shown to have significantly increased levels of plasma LDL-cholesterol and impaired circulating LDLc clearance through hepatocyte LDLR. This chapter reports, for the first time, that Commd1 acts as an adaptor protein to mediate trafficking of the LDLR in hepatocytes and further advocates a more common role of Commd1 in vesicular transport. Chapter 7 provides more insights into Commd1’s actions in the liver. The long-term (20 weeks) effects of HFC-feeding on liver steatosis in Commd1∆Hep mice are described. Finally, Chapter 8 summarizes the findings presented in this thesis and discusses them. 7 CHAPTER 1 General introduction General introduction GENERAL introDuction 1 Obesity is a growing problem worldwide. In European countries its prevalence has increased three-fold in the past 30 years, resulting in over 50% of individuals being overweight and over 20% being obese today. Not only does it affect more and more adults, but children are also more frequently being diagnosed with obesity as well. According to the World Health Organization (WHO), in 2011 more than 40 million under five-years-old children were overweight. Moreover, the WHO also reported that the shocking number of approximately 2.8 million adults die every year because of obesity- and overweight-related health problems, and that globally there are more deaths recorded as a results of obesity or overweight than due to the malnutrition. The increased fat accumulation (which is most commonly manifested as an elevation in body mass index (BMI)) is therefore considered one of the major risk factors for developing a number of health problems and/or severe chronic diseases, including diabetes, hypercholesterolemia, cardiovascular diseases (CVD), asthma, arthritis, or even cancer. NAFLD A high percentage of the obese population develops non-alcoholic fatty liver disease (NAFLD). This hepatic disorder comprises features ranging from a benign and simple fatty liver disease called steatosis to much more severe stages, such as cirrhosis or even hepatocellular carcinoma (HCC). NAFLD susceptibility originates from a mixture of factors, from genetic to environmental and lifestyle [1]. The initial histological abnormality of NAFLD is hepatic steatosis, as seen by increased liver triglyceride accumulation, a major hallmark of NAFLD [1, 2]. Furthermore, obese steatotic patients also present with increased adipose tissue-derived free fatty acid (FFA) influx into the liver and elevated de novo lipogenesis (DNL) [3, 4]. The hepatic contribution of triglycerides (TGs) originating from DNL in individuals with NAFLD is approximately 26% [3], whereas in the healthy population DNL accounts for less than 5% of hepatic TG formation [5, 6]. Not only are lipid synthesis pathways affected during NAFLD, but the fatty acid oxidation and secretion is also impaired [7, 8]. Since FFA are thought to be toxic, because they increase oxidative stress and activate inflammatory pathways [9], the described defects in lipid metabolism, which are often accompanied
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