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The Influence of Adenoviral Infection and the Group VIA Calcium- Independent Phospholipase A2 on Hepatic Lipid Metabolism

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The Influence of Adenoviral Infection and the Group VIA Calcium- Independent Phospholipase A2 on Hepatic Lipid Metabolism Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2007 The Influence of Adenoviral Infection and the Group VIA Calcium- Independent Phospholipase A2 on Hepatic Lipid Metabolism William Palmer Wilkins III Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Biochemistry, Biophysics, and Structural Biology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1369 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © William Palmer Wilkins, III, 2008 All Rights Reserved THE INFLUENCE OF ADENOVIRAL INFECTION AND THE GROUP VIA CALCIUM-INDEPENDENT PHOSPHOLIPASE A2 ON HEPATIC LIPID METABOLISM A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by WILLIAM PALMER WILKINS, III Bachelor of Science, Hampden-Sydney College, 1996 Director: SUZANNE E. BARBOUR, PHD PROFESSOR, DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY Virginia Commonwealth University Richmond, Virginia MAY 2008 ii Acknowledgement I wish to thank my thesis advisor Dr. Suzanne Barbour for her consistent support, guidance and belief in my abilities as a scientist during my years of graduate study. I wish to acknowledge my mother Brenda Burke McGehee, father William Palmer Wilkins, Jr. and close friends for their support and encouragement throughout my life. I wish to thank the following committee members for their efforts during my training: Dr. Shobha Ghosh, Dr. Gregorio Gil, Dr. Steve Sawyer and Dr. Sarah Spiegel. Collaborative studies with Dr. Gil and Dr. Philip Hylemon and their laboratories have been an invaluable asset during my training. I wish to acknowledge the dedication and hard work of Pat Bohdan, Emily Gurley and Elaine Studer of Dr. Hylemon’s laboratory as well as the assistance of Kaye Redford and Dr. W. M. Pandak with the plasma analyses. Finally, I wish to acknowledge the friendships developed with and support of those graduate students, especially Rachael Griffiths and Dr. Alex Manguikian, who have worked alongside me during these years “at the bench.” iii Table of Contents Page Acknowledgements............................................................................................................. ii List of Tables .................................................................................................................... vii List of Figures.................................................................................................................. viii List of Abbreviations ...........................................................................................................x Chapter 1 General Introduction..........................................................................................1 Examples of the influence of lipids on cellular processes and signaling ......2 Sterol regulatory element-binding protein ....................................................4 Early studies characterizing SREBP .............................................................9 Regulation of SREBP by PUFA..................................................................10 SREBP and insulin signaling ......................................................................12 Influence of microorganisms on lipid metabolism and the biology of Adenovirus-5.........................................................................................11 Review of the group VIA calcium-independent phospholipase A2 ............17 Glycerophospholipids and phospholipases...........................................17 iPLA2 structure......................................................................................20 Alternative splicing and iPLA2 isoforms...............................................25 Regulation of iPLA2 activity .................................................................26 Regulation of iPLA2 expression............................................................31 iv Biological functions of iPLA2 .....................................................................32 Glycerophospholipid Metabolism.........................................................33 Acyl chain remodeling ..................................................................33 Regulation of glycerophospholipid mass ......................................34 Arachidonic acid metabolism and eicosanoid production.............35 Pathogenesis and innate immune response ...........................................37 Innate immune response................................................................37 Pathogenesis of Pseudomonas aeruginosa....................................39 Calcium signaling and homeostasis ......................................................39 Cell proliferation, survival and apoptosis..............................................41 iPLA2 and cell apoptosis ...............................................................41 iPLA2 and cell survival, growth and proliferation ........................46 iPLA2 in metabolism .............................................................................48 iPLA2 and glucose-stimulated insulin secretion............................48 iPLA2 and adipocyte/hepatocyte biology......................................50 iPLA2 in mitochondrial fuction and energy homeostasis..............55 iPLA2 in neurological diseases..............................................................55 Summary and perspectives....................................................................57 The novel PI3K inhibitor PX-866 ...............................................................61 Rationale for studies....................................................................................64 v 2 The influence of replication-deficient adenovirus-5 on hepatic lipid metabolism ..................................................................................................65 Introduction .................................................................................................67 Materials and Methods ................................................................................68 Results .........................................................................................................74 Discussion .................................................................................................100 3 The group VIA calcium-independent phospholipase A2 as a novel regulator of sterol regulatory element-binding proteins................................................103 Introduction ...............................................................................................105 Materials and Methods ..............................................................................109 Results .......................................................................................................116 iPLA2 overexpression suppresses SREBP1 expression and activity...116 iPLA2 suppresses expression of SREBP1 target genes.......................121 Analysis of SREBP1 in CHO cells overexpressing iPLA2 and in CHO cells with low iPLA2 activity...............................................................124 Discussion .................................................................................................135 4 The influence of the novel phosphatidylinositol 3-kinase inhibitor PX-866 on systemic and hepatic basal lipid metabolism ............................................142 Introduction ...............................................................................................144 vi Materials and Methods ..............................................................................146 Results .......................................................................................................148 Discussion .................................................................................................156 5 Concluding Remarks......................................................................................160 Reference list ...................................................................................................................168 Vita...................................................................................................................................206 vii List of Tables Page Table 1: Biological functions of iPLA2. ............................................................................59 Table 2: iPLA2 overexpression decreases fatty acid synthesis in HepG2 cells. .............123 Table 3: Chemical inhibition of iPLA2 increases SREBP-mediated gene expression in CHO cells.........................................................................................................................131 viii List of Figures Page Figure 1: SREBP gene targets..............................................................................................8 Figure 2: Depiction of structure of (A) Group VIA PLA2 (iPLA2β) and (B) Group VIB PLA2 (iPLA2γ) ...................................................................................................................23 Figure 4: iPLA2β ATP binding mutant has minimal catalytic activity..............................29 Figure 5: iPLA2 regulates SREBP .....................................................................................53
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