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Apolipoprotein E in Diabetic Dyslipidemia and Atherosclerosis

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Apolipoprotein E in Diabetic Dyslipidemia and Atherosclerosis APOLIPOPROTEIN E IN DIABETIC DYSLIPIDEMIA AND ATHEROSCLEROSIS Lance A Johnson A dissertation submitted to the faculty of the department of Cellular and Molecular Pathology at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chapel Hill 2011 Approved by: Oscar Alzate, PhD Jonathon Homeister, MD, PhD Chris Mack, PhD Nobuyo Maeda, PhD Patrick Sullivan, PhD © 2011 Lance A Johnson ALL RIGHTS RESERVED ii ABSTRACT LANCE JOHNSON: Apolipoprotein E in Diabetic Dyslipidemia and Atherosclerosis (Under the direction of Nobuyo Maeda, PhD) Each year, cardiovascular disease (CVD) kills more Americans than any other cause of death. The majority of the diseases contributing to CVD can be traced back to the pathological process of atherosclerosis, in which fatty material collects along the walls of arteries, limiting flexibility and obstructing blood flow. Plasma lipids, particularly in the form of low-density lipoprotein (LDL) cholesterol, contribute significantly to the formation of atherosclerotic plaques and are an important determinant of CVD risk. Thus, it is critical to understand the roles of the crucial components of normal lipoprotein metabolism that regulate plasma lipids, such as apolipoprotein (apo) B, apoE and the LDL receptor. In addition, patients with diabetes are two to four times as likely to develop CVD as non-diabetic patients. One important reason for this discrepancy is the process of diabetic dyslipidemia – a cluster of harmful changes to normal lipoprotein metabolism commonly seen in patients with diabetes. ApoE is the primary ligand for several lipoprotein receptors, making it a crucial component in the clearance of lipid from the circulation and a major determinant of plasma cholesterol and cardiovascular disease risk. The APOE gene is polymorphic, resulting in production of three common isoforms: ApoE2, E3, and E4. In addition to its role in lipoprotein metabolism, recent findings have also suggested a role for ApoE in glucose metabolism. In Chapter 2, I examine the role of apoE3 and apoE4 during the process of diabetic dyslipidemia and atherosclerosis. Similarly, Chapter iii 3 focuses on the crucial interaction between apoE and the LDLR in the background of diabetes. In Chapter 4, I explore the increased risk of CVD in patients with diabetes in detail, focusing on the various models of diabetic atherosclerosis available to researchers and how they may help understand the cause of this risk. Finally, in Chapter 6 I provide a supplemental examination of the the role of apoB, and in particular the LDLR binding region of apoB100, in the development of hyperlipidemia and atherosclerosis. Together, this work highlights the importance and interconnectedness of glucose and lipid metabolism, and sheds new light on the critical role of apolipoprotein E in the development of dyslipidemia and atherosclerosis during diabetes. iv ACKNOWLEDGMENTS Nobuyo literally has an open door policy. Over the past few years I have walked into her office countless times to ask questions and advice. I usually begin with some variation of the phrase “Nobuyo, can I bother you for a minute?” A credit to her patience and willingness to help, she has never once said “No”, “Not right now”, or even “Could you come back later?” She has answered every single question I have come up with (although sometimes with another question), and I greatly appreciate the many hours she has spent mentoring me along the way. In addition to their penchant for teaching, both Nobuyo and Oliver easily inspire without words. A graduate student could not ask for a better example of the hard work and dedication that it takes to be a successful scientist. But long hours are not enough, and the passion, the curiosity, and the love of science that Nobuyo and Oliver demonstrate is absolutely infectious. I would also like to thank the members of my thesis committee: Drs. Jon Homeister, Chris Mack, Oscar Alzate and Patrick Sullivan. As cardiovascular researchers, Jon and Chris have suggested several pertinent and crucial experiments along the way – and while Oscar’s recommendations have had an outsider’s (protein chemist’s) view, they have always been spot on. I’d like to especially thank Patrick, who has generously offered his time and support and has been an invaluable source of advice as I transition into an area of research that he helped launch with his own important work. Dr. Bill Coleman and Dorothy Poteat also deserve v special thanks for their willingness to answer all my questions and their enormous help guiding me through every different stage of graduate school. I also owe big thanks to the ‘big fella’. When I started working in the lab, Mike was quick to take me under his wing. Mike is as genuine, honest and straightforward person as you’ll meet. He is as quick to admit an experimental error as he is to take credit for an experimental success – and both were equally important during the learning process. And of course for every bit of information or technique I’ve learned from Mike, there have been several good laughs. I’ve been privileged to work alongside, and become friends with Mike, Jen - who I actually owe my career in science to (she hired me as a technician) - and their family. My other mentor came all the way from Spain. I was incredibly lucky to have Jose here in the lab and working on a similar project. He picked up on apoE research almost as quickly as he picked up dirty English words and jokes. I often relied on his knowledge and experience, as well as his humor, to help me through my days in the lab. I’ve also been fortunate enough to have several excellent postdocs around during my time as a graduate student. I never hesitated to ask Kumar, Yi, Hirofumi and Feng for a protocol, reagent or advice; and they never hesitated to help. Of course, this lab wouldn’t function without Sylvia, Jen, Svetlana, Jenny, Shin-Ja and Ron here to run it. All of them work incredibly hard to keep things going smoothly, but still always managed to make time and lend a hand when I needed it. My fellow graduate students have all helped me carry the load – assisting with experiments, providing ideas and advice, and just as importantly, being there to listen to all the complaints and help deal with the inevitable failures that are a part of science. In particular, I owe great thanks to Ray and Avani, who never shied away from helping with an experiment or a practical joke. You guys have been a great help in the lab and great friends vi outside of it. I also had a great deal of assistance from a bright young group of future scientists. Marcus, Taylor, Sabrina, and Melissa – they made me feel old, but have all helped tremendously. Most of all, I want to thank my wife, Ryann, who has been there from the beginning of my graduate career, and without whom there may never have been an end. I was also fortunate enough to marry into a generous, intelligent family – and Ryann’s parents, Donna and Glynn, have provided incredible support and encouragement during my graduate career. Ryann has always been amazingly supportive, quick to rearrange her schedule when my schedule in the lab needed it – and as Nobuyo would be happy to know, she routinely told me to ‘just go to the lab and do some work’ on weekends (although it was mostly to get me out of her hair). She has pushed me to work hard, celebrated when I succeed, and picked me up and brushed me off when I haven’t. Even when every experiment seems to fail, every hypothesis seems to be wrong, and every reviewer seems to be out to get me, I can still go home at night and feel like the luckiest scientist on Earth. vii TABLE OF CONTENTS LIST OF TABLES ................................................................................................................... xi LIST OF FIGURES ............................................................................................................... xii LIST OF ABBREVIATIONS ............................................................................................... xiv Chapter I. INTRODUCTION ................................................................................................................. 1 1.1 Cardiovascular Disease ......................................................................................... 2 1.2 Lipoprotein Metabolism ......................................................................................... 2 1.3 Apolipoprotein B .................................................................................................... 5 1.4 Apolipoprotein E .................................................................................................... 6 1.5 Mouse models of human apoE ............................................................................. 13 1.6 Low Density Lipoprotein Receptor ..................................................................... 16 1.7 Overexpression of the LDLR ............................................................................... 19 1.8 Diabetes ................................................................................................................ 22 1.9 Mouse Models of Diabetes .................................................................................. 23 1.10 Diabetic Dyslipidemia ........................................................................................ 25 1.11 ApoE in Diabetes ................................................................................................ 28 REFERENCES ..........................................................................................................
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