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Inherent Flaw of Cholesterol Processing in Cell

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Inherent Flaw of Cholesterol Processing in Cell INHERENT FLAW OF CHOLESTEROL PROCESSING IN CELL CULTURE AND IN VIVO MODELS OF CYSTIC FIBROSIS by NICOLE MARIE WHITE Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Thomas J Kelley Department of Pharmacology Case Western Reserve University January 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION To my parents who exemplify the contentment and fulfillment in life that I aspire to, and to Chris whose continued support and belief of me served as a buoy when I faltered. TABLE OF CONTENTS LIST OF FIGURES .....................................................................................................................iii LIST OF ABBREVIATIONS......................................................................................................... iv ACKNOWLEDGMENTS.............................................................................................................. vi ABSTRACT................................................................................................................................ix CHAPTER 1: BACKGROUND...................................................................................................... 1 The inflammatory response in cystic fibrosis................................................................... 1 Altered cell signaling events in cystic fibrosis .................................................................. 5 Role of the isoprenoid/cholesterol pathway in cystic fibrosis disease pathology .......... 8 Evidence of altered metabolism in cystic fibrosis .......................................................... 12 Niemann-Pick disease type C as a mechanistic model of the cystic fibrosis inflammatory response ..................................................................................................... 16 Statement of Purpose........................................................................................................ 18 CHAPTER 2: MECHANISTIC SIMILARITIES BETWEEN CULTURED CELL MODELS OF CYSTIC FIBROSIS AND NIEMANN-PICK TYPE C................................................................................... 27 Abstract.............................................................................................................................. 27 Introduction....................................................................................................................... 28 Methods.............................................................................................................................. 30 Results ................................................................................................................................ 33 CF-Like Cell Signaling Alterations in NPC Fibroblasts .............................................................33 An Examination of NPC-Like Phenotypes in CF Model Cells ....................................................34 Discussion........................................................................................................................... 37 CHAPTER 3: ALTERED CHOLESTEROL HOMEOSTASIS IN CULTURED AND IN VIVO MODELS OF CYSTIC FIBROSIS .................................................................................................................... 58 Abstract.............................................................................................................................. 58 Introduction....................................................................................................................... 59 Methods.............................................................................................................................. 61 Results ................................................................................................................................ 69 Discussion........................................................................................................................... 75 i CHAPTER 4: ACUTE AND CHRONIC INHIBITION OF CFTR FUNCTION CAUSES CHOLESTEROL ACCUMULATION...................................................................................................................... 98 Abstract.............................................................................................................................. 98 Introduction....................................................................................................................... 99 Methods............................................................................................................................ 102 Results .............................................................................................................................. 107 Acute inhibition of CFTR function initiates altered cholesterol processing..............................107 Link of CFTR function in mouse models to disrupted cholesterol processing...........................110 Discussion......................................................................................................................... 113 CHAPTER 5: SUMMARY, FUTURE DIRECTIONS, CONCLUSIONS.......................................... 136 Summary.......................................................................................................................... 136 Implications for similar pathways important in disease pathology of CF and NPC.................136 Deficient cholesterol transport elicits a CF-like cytokine production.......................................139 Isoprenoid/cholesterol synthesis as a mechanism for cell signaling alterations in CF.............140 Cholesterol relationship to CF fatty acid deficiency .................................................................142 CF intestinal phenotype.............................................................................................................146 Global CF metabolic disorders .................................................................................................148 Preliminary Results and Future Directions.................................................................. 150 Indirect cholesterol accumulation caused by ceramide accumulation......................................152 Altered endosomal pH as a cellular trigger for cholesterol accumulation ...............................154 Altered endosomal calcium as a cellular trigger for cholesterol accumulation........................155 REFERENCE LIST.................................................................................................................. 168 ii LIST OF FIGURES Figure 1-1. De novo isoprenoid/cholesterol synthesis pathway. ...................................................21 Figure 1-2. Sterol regulatory element binding protein cholesterol regulation...............................23 Figure 1-3. Major routes of cholesterol and CFTR trafficking......................................................25 Figure 2-1. Reduced induction of (NOS2) in NPC compared with wt fibroblasts.......................42 Figure 2-2. Increased STAT1 protein expression in NPC compared with wt fibroblasts. ...........44 Figure 2-3. Western blot of increased RhoA expression in NPC and CF model systems............46 Figure 2-4. Decreased Smad3 expression in NPC and CF model systems...................................48 Figure 2-5. Increased filipin staining in CF epithelial cells compared to controls........................50 Figure 2-6. RhoA and STAT1 protein expression in IB3 (CF) and S9 (CFTR-corrected) cells. .52 Figure 2-7. ASM activity in pCEPR (CF) and pCEP (wt) 9/HTEo cells. ....................................54 Figure 2-8. Increased NPC1 mRNA levels in CF model cells compared with controls...............56 Figure 3-1. Unesterified cholesterol accumulation in CF tissue...................................................82 Figure 3-2. NBD-cholesterol accumulation in two CF cell culture systems. ...............................84 Figure 3-3. Lysosomal storage of NBD-cholesterol in CF cells....................................................86 Figure 3-4. Microelectrode determination of membrane cholesterol content...............................88 Figure 3-5. Increased sterol response element (SRE) response in CF cells...................................90 Figure 3-6. Increased de novo cholesterol synthesis in Cftr-/- mouse tissue.................................92 Figure 3-7. Impaired cholesterol transport causes CF related cytokine release. ...........................94 Figure 3-8. The role of DHA in cholesterol transport. ..................................................................96 Figure 4-1. NBD-cholesterol accumulation in INH-172 treated control epithelial cells.............122 Figure 4-2. Increased SRE response in INH-172 treated control epithelial cells. .......................124 Figure 4-3. Microelectrode determination of INH-172 treated cell membrane cholesterol. .......126 Figure 4-4. Microelectrode
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