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University of Florida Thesis Or Dissertation Formatting RECIPROCAL RELATIONSHIP BETWEEN DIETARY IRON AND COPPER AND WHOLE-BODY METABOLISM OF BOTH MINERALS By JUNG-HEUN HA A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2016 © 2016 Jung-Heun Ha To Lord and my family ACKNOWLEDGMENTS Although only my name is written in this dissertation, however, there are abundant people involved in this publication. I have debts to all of these great people who supported to fabricate this dissertation. My first and important gratitude is to my major mentor, Dr. James F. Collins. I have huge fortunate to have an advisor who gave me a chance to learn science with sincere guidance for every step. Dr. Collins showed unlimited patience, gentleness and support and these are direct reasons to finish this dissertation. I want to learn his excellence in academia and personality, so if I have a chance to become a principal investigator later, I would like to manage my lab in his ways. Besides my advisor, I would like to thank the rest of my thesis committee: Dr. Mitchell D. Knutson, Dr. Bobbi Langkamp-Henken and Dr. Volker Mai, for detailed discussion, insightful comments, technical supports and encouragement to widen my research to variety perspectives. Dr. Caglar Doguer was the most helpful friend in this dissertation. He gave me numerous helpful comments when I transferred to Dr. Collins lab and also helped to generate significant amount of data in this dissertation. Also, I owed to Min-Hyun Kim, Martin Alla, Shireen R. Flores and Xiaoyu Wang since they helped me in many aspects. My sincere thanks also go to Dr. Myoung-Sool Do, Department of Life Sciences in Handong University. He sparked my research interest in molecular nutrition. His life challenged me how to live a disciple in this world as a scientist. I am also grateful to Dr. Vernon Rayner, worked in the Rowett Research Institute. Dr. Rayner's insightful comments and constructive philosophies in science of my 4 previous research were positively affected my research career. He also gave me helpful comment for this dissertation. I am also indebted to Dr. Chang-Woo Song, Korea Institute of Toxicology. His life showed me the sincere responsibility to lab members as a principle investigator and a Christian. I am able to writing this dissertation with his responsible sacrifice in the Institute. Most importantly, none of this work would be accomplished without love and patience of my family. My family showed me everlasting love, devotional praying, unselfish sacrifice and support all these years. I cannot express my grateful heart with just few words to my family. My parents showed me unconditional love and support. I am proud since I am your son and appreciate to give me a chance to prove and improve myself. Though I cannot see my grandmother again, I want to appreciate for her dedicated attitude for me. I had a huge appreciation to my wife, Sun Young Jeong, who has thoughtful enough to understand my filibuster to housework with variety supports for this degree. Also, I would like to appreciate to my sons, Ijoon (John) and Isan (Joesph) since they are good news makers during my degree. I would like to congratulate my brother Dr. Dongheon Ha received a PhD degree in this spring and wish to bless his new life. Thank you God it is graduation. Now I know there are no higher mountains and waves as long as you are my side. 5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 9 LIST OF FIGURES ........................................................................................................ 10 ABSTRACT ................................................................................................................... 16 CHAPTER 1 LITERATURE REVIEW .......................................................................................... 18 Iron-Related Disorders: Iron Deficiency .................................................................. 18 Iron-Related Disorders: Iron Overload .................................................................... 19 Intestinal Iron Absorption: Heme Iron ..................................................................... 20 Intestinal Iron Absorption: Nonheme Iron................................................................ 21 Main Functions of Copper ....................................................................................... 21 Copper Related Disorders: Copper Deficiency ....................................................... 22 Copper Related Disorders: Copper Overload ......................................................... 23 Intestinal Copper Absorption ................................................................................... 24 Iron and Copper Interactions .................................................................................. 25 Copper Metabolism in Dietary Iron-Deficiency and Iron-Overload Models ............. 26 Iron Metabolism During Dietary Copper-Deficiency ................................................ 27 2 MATERIALS AND METHODS ................................................................................ 30 Animal Experiments ................................................................................................ 30 Determination of Iron Status and Hepatic Mineral Concentrations ......................... 31 Serum Erythropoietin Measurement ....................................................................... 32 para-Phenylenediamine (pPD) Assay ..................................................................... 32 Cell Culture and Development of Atp7a KD IEC-6 and Caco-2 Cells ..................... 32 Iron Transport Studies ............................................................................................ 34 Mineral Analysis ...................................................................................................... 35 Atomic Absorption Spectrometry ...................................................................... 35 Inductive-Coupled Plasma Mass Spectrometry ................................................ 35 qRT-PCR ................................................................................................................ 35 FOX Activity Assay ................................................................................................. 36 Ferrireductase Activity Assay .................................................................................. 36 Protein Isolation and Immunoblotting ...................................................................... 36 Determination of Copper Absorption and Distribution ............................................. 37 Statistical Analysis .................................................................................................. 38 3 HIGH-IRON CONSUMPTION IMPAIRS GROWTH AND CAUSES COPPER- DEFICIENCY ANEMIA IN WEANLING SPRAGUE-DAWLEY RATS ..................... 46 6 Introduction ............................................................................................................. 46 Results .................................................................................................................... 48 Growth Rates and Organ Weights Differed Among Experimental Groups ....... 48 Low- and High-Iron Consumption Altered Hematological Parameters ............. 48 Renal Epo Expression Was Induced by Copper Deprivation in Iron-Deficient and Iron-Loaded Rats ................................................................................... 49 The Erythroid Iron Regulator, Erfe, Was Induced by Copper Deprivation in the Spleens of Iron-Deficient Rats ................................................................. 49 Hepatic Nonheme Iron Loading Increased in the HFe/HCu Group ................... 50 High-Iron Feeding Increased Tissue Iron Levels .............................................. 51 High-Iron Feeding Caused Systemic Copper Deficiency .................................. 51 Discussion .............................................................................................................. 52 4 DIETARY IRON OVERLOAD CAUSES COPPER DEFICIENCY IN WEANLING C57BL/6 MICE BUT INTESTINAL COPPER ABSORPTION IS NORMAL ............. 65 Introduction ............................................................................................................. 65 Results .................................................................................................................... 68 High-Iron Consumption Caused Mortality, Growth Retardation and Cardiac Hypertrophy ................................................................................................... 68 Dietary Iron and Copper Concentrations Affected Hematological Parameters and Transferrin Saturation ......................................................... 69 High-Iron Intake Induced Hepatic Hepcidin Expression with increased Hepatic Iron Accumulation ............................................................................ 69 High-Iron and Copper Affects Iron Homeostasis-Related Gene Expression .... 69 Dietary Iron and Copper Altered Renal Erythropoietin Expression ................... 70 Hepatic Copper Distribution and Cp Activity ..................................................... 70 64Cu Absorption and Distribution Were Not Altered by High-Iron
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