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The NLRC4 Inflammasome and Its Regulation of Liver Disease

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The NLRC4 Inflammasome and Its Regulation of Liver Disease THE NLRC4 INFLAMMASOME AND ITS REGULATION OF LIVER DISEASE PATHOGENESIS by DAVID ANDREW DESANTIS Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: Colleen M. Croniger, Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of DAVID ANDREW DESANTIS candidate for the degree of Doctor of Philosophy* __________________ (signed) Noa Noy, PhD (Committee Chair) Colleen Croniger, PhD Laura Nagy, PhD George Dubyak, PhD Date of Defense May 13, 2015 *We also certify the written approval has been obtained for any proprietary material contained therein. ii DEDICATION I dedicate this work to my mother, father, wife, and children. To my mother, who taught me education is a priority. Knowledge has come first, everything else has followed. To my father, who showed me the value of a strong work ethic. I derive all my persistence from you. To my wife, Caitlin, without whom I would most certainly not have achieved this milestone. Your love, strength, and support has given me this wonderful opportunity. I am forever grateful. To my children, Sophie and Daniel. The moment I laid eyes on you I knew every achievement thereafter would be for you. This body of work is no different. iii TABLE OF CONTENTS Table of Contents .......................................................................................................iv List of Tables .............................................................................................................x List of Figures ............................................................................................................xi Preface........................................................................................................................xv Acknowledgements ....................................................................................................xvi List of Abbreviations .................................................................................................xviii Abstract ......................................................................................................................xxiii CHAPTER 1: THE LIVER 1.1. Human Liver Anatomy ......................................................................................1 1.1.1. Gross Anatomy of the Human Liver ........................................................1 1.1.2. Microscopic Anatomy of the Human Liver .............................................4 1.2. Mouse Liver Anatomy .......................................................................................8 1.3. Cells of the Liver ...............................................................................................8 1.3.1. Hepatocyte ...............................................................................................8 1.3.1.1. Lipid Synthesis ..............................................................................9 1.3.1.2. Lipid Oxidation .............................................................................9 1.3.1.3. Lipid Transport..............................................................................10 1.3.1.4. Detoxification ................................................................................10 iv 1.3.2. Kupffer Cell .............................................................................................13 1.3.3. Hepatic Stellate Cell ................................................................................14 1.3.4. Sinusoidal Endothelial Cell......................................................................16 CHAPTER 2: DISEASES OF THE LIVER 2.1. Overview ...........................................................................................................18 2.2. Alcoholic Liver Disease ....................................................................................18 2.3. Nonalcoholic Fatty Liver Disease .....................................................................19 CHAPTER 3: MURINE MODELS OF LIVER INJURY 3.1. Xenobiotic .........................................................................................................22 3.1.1. Carbon Tetrachloride ...............................................................................22 3.1.2. Concanavalin A ........................................................................................23 3.1.3. Ethanol .....................................................................................................25 3.2. Surgical ..............................................................................................................28 3.2.1. Bile Duct Ligation....................................................................................28 3.3. Dietary ...............................................................................................................29 3.3.1. High-Fat Diet ...........................................................................................29 3.3.2. Methionine and Choline Deficient Diet ...................................................30 CHAPTER 4: LIVER REGENERATION 4.1. Overview ...........................................................................................................32 4.2. Two-Thirds Partial Hepatectomy ......................................................................35 v 4.3. Other Models of Liver Regeneration .................................................................44 4.3.1. Concanavalin A ........................................................................................44 4.3.2. Carbon Tetrachloride ...............................................................................45 4.3.3. D-galactosamine ......................................................................................45 CHAPTER 5: MOUSE GENETICS 5.1. Inbred Genetic Mouse Strains ...........................................................................47 5.2. Chromosome Substitution and Congenic Mouse Strains ..................................48 CHAPTER 6: IMMUNITY 6.1. Overview ...........................................................................................................53 6.2. The Innate Immune Response ...........................................................................53 6.2.1. Neutrophils ...............................................................................................54 6.2.2. Cytokines .................................................................................................55 CHAPTER 7: THE INFLAMMASOME 7.1. Overview ...........................................................................................................57 7.2. Inflammasome Structure ...................................................................................58 7.3. NLR Family .......................................................................................................60 7.4. Inflammasome Function ....................................................................................65 7.4.1. DAMPs and PAMPs ................................................................................66 7.4.2. Caspase-1 .................................................................................................68 7.4.3. Apoptosis .................................................................................................69 vi 7.4.3.1. Overview .......................................................................................69 7.4.3.2. Extrinsic Apoptotic Pathway ........................................................71 7.4.3.3. Intrinsic Apoptotic Pathway ..........................................................72 7.4.3.4. Perforin-Granzyme-Dependent Apoptotic Pathway .....................73 7.4.4. Pyroptosis .................................................................................................74 7.4.5. Interleukin-1β ...........................................................................................74 7.4.6. Interleukin-18 ...........................................................................................79 7.4.7. Interleukin-6 .............................................................................................81 7.5. NLRC4 Inflammasome .....................................................................................87 7.5.1. Overview ..................................................................................................87 7.5.2. Structure and Assembly of the NAIP/NLRC4 Inflammasome ................87 7.5.3. NLRC4-Mediated Pyroptosis...................................................................91 7.5.4. Current Model ..........................................................................................93 CHAPTER 8: PUBLICATION 8.1. DeSantis DA, Lee P, Doerner SK, Ko CW, Kawasoe JH, Hill-Baskin AE, Ernest SR, Bhargava P, Hur KY, Cresci GA, Pritchard MT, Lee CH, Nagy LE, Nadeau JH, Croniger CM. Genetic resistance to liver fibrosis on A/J mouse chromosome 17. Alcohol Clin Exp Res. 2013 Oct;37(10):1668-79. ......94 CHAPTER 9: PUBLICATION 9.1. DeSantis DA, Ko CW, Wang L, Lee PL, Croniger CM. Constitutive Activation of the Nlrc4 Inflammasome Prevents Hepatic Fibrosis and vii Promotes Hepatic Regeneration after Partial Hepatectomy. Submitted to Fibrogenesis Tissue Repair. 4/15/15. ................................................................144 CHAPTER 10: DISCUSSION, IMPLICATIONS, AND FUTURE DIRECTIONS 10.1. Identification of Novel Candidate Genes in the Progression of Liver Injury ...202
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