Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2020 Hepatic peroxisome and its implications on cardiac function, inflammation and aging Kerui Huang Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Recommended Citation Huang, Kerui, "Hepatic peroxisome and its implications on cardiac function, inflammation and aging" (2020). Graduate Theses and Dissertations. 18329. https://lib.dr.iastate.edu/etd/18329 This Thesis is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Hepatic peroxisome and its implications on cardiac function, inflammation and aging by Kerui Huang A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Genetics and Genomics Program of Study Committee: Hua Bai, Major Professor Stephen Howell Kristen Johansen Maura McGrail Marna Yandeau-Nelson The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2020 Copyright © Kerui Huang, 2020. All rights reserved. ii DEDICATION I would like to dedicate this thesis to my parents, who always give me full support even under difficult times. Also, my husband, who endured the same level of stress as a PhD student yet managed to give guidance and encouragement. I would also like to dedicate this thesis to my dear friends for making this journey enjoyable. iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS ............................................................................................................................ v ABSTRACT ................................................................................................................................................. vi CHAPTER 1. GENERAL INTRODUCTION .............................................................................................. 1 CHAPTER 2. LIVER HEPATOKINES AND PEROXISOMES AS THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASES ..................................................................................................... 2 2.1 Liver dysfunctions that cause cardiac diseases ..................................................................... 3 2.2 Hepatokines linked to cardiovascular diseases ..................................................................... 5 2.3 Conclusion ............................................................................................................................. 7 2.4 References ............................................................................................................................. 7 CHAPTER 3. FRIENDS OR FOES? THE ROLE OF PEROXISOMES IN INFLAMMAGING ............. 10 3.1 Introduction ......................................................................................................................... 10 3.2 Peroxisomes as a source and sink for reactive oxygen species (ROS) ............................... 11 3.3 What happens to redox level when peroxisome is impaired? ............................................. 13 3.4 Peroxisomes and aging ........................................................................................................ 15 3.5 References ........................................................................................................................... 16 CHAPTER 4. RIBOTAG TRANSLATOMIC PROFILING OF DROSOPHILA OENOCYTES UNDER AGING AND OXIDATIVE STRESS ......................................................................................... 19 4.1 Abstract ............................................................................................................................... 20 4.2 Background ......................................................................................................................... 21 4.3 Results ................................................................................................................................. 23 4.4 Discussion ........................................................................................................................... 36 4.5 Conclusion ........................................................................................................................... 43 4.6 Methods ............................................................................................................................... 43 4.7 References ........................................................................................................................... 48 4.8 Figures ................................................................................................................................. 56 iv CHAPTER 5. IMPAIRED PEROXISOMAL IMPORT IN DROSOPHILA OENOCYTES CAUSES CARDIAC DYSFUNCTION BY INDUCING UPD3 AS A PEROXIKINE ............................ 69 5.1 Abstract ............................................................................................................................... 69 5.2 Introduction ......................................................................................................................... 70 5.3 Results ................................................................................................................................. 72 5.4 Discussion ........................................................................................................................... 85 5.5 Methods ............................................................................................................................... 88 5.6 References ........................................................................................................................... 95 5.7 Figures ............................................................................................................................... 100 5.8 Appendix ........................................................................................................................... 119 CHAPTER 6. PEROXISOME IMPORT STRESS IMPAIRS RIBOSOME BIOGENESIS IN DROSOPHILA AND HUMAN CELLS........................................................ 120 6.1 Abstract ............................................................................................................................. 120 6.2 Introduction ....................................................................................................................... 121 6.3 Results ............................................................................................................................... 124 6.4 Discussion ......................................................................................................................... 137 6.5 Methods ............................................................................................................................. 143 6.6 References ......................................................................................................................... 151 6.7 Figures ............................................................................................................................... 160 6.8 Appendix ........................................................................................................................... 172 CHAPTER 7. CONCLUSIONS ............................................................................................................... 173 v ACKNOWLEDGMENTS I would like to thank my committee chair Dr. Hua Bai for his support, advice, encouragement, and guidance through my PhD. He saw the raw potential in me and guide me to gain confidence and to become a competent scientist. His passion for science will always inspire me and I will take the skills I learned throughout my scientific career. I would also like to thank my former committee member, Prof. Linda Ambrosio who helped me in so many ways and my committee members: Prof. Maura McGrail, Prof. Marna Yandeau-Nelson, Prof. Stephen Howell and Prof. Kristen Johansen - for their time and commitment throughout the course of this research. In addition, I would also like to thank the GDCB department faculty and staff for making my time at Iowa State University a wonderful and unforgettable experience. vi ABSTRACT Aging is characterized by a chronic, low-grade inflammation, which is a major risk factor for cardiovascular diseases. As one of the important metabolic centers, the liver shows age- related dysregulation of lipid metabolism, increased inflammation, and oxidative stress response. It remains poorly understood whether pro-inflammatory factors released from liver contribute to the non-autonomous regulation of age-related cardiac dysfunction. We showed that Drosophila oenocytes share molecular similarities and age-related changes with mammalian livers. We perform translatomic profiling on Drosophila oenocytes to understand age- and stress-regulated gene expression changes. We show that aging down- regulates oxidative phosphorylation, ribosome, proteasome and peroxisomal biogenesis in oenocytes, whereas innate