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Effects of Conjugated Linoleic Acid Isomers on Eicosanoid Metabolism in Kidney

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Effects of Conjugated Linoleic Acid Isomers on Eicosanoid Metabolism in Kidney Effects of Conjugated Linoleic Acid Isomers on Eicosanoid Metabolism in Kidney and Liver Tissues of Obese Zucker Rats by Hong Shi A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfilment of the requirements of the degree of MASTER OF SCIENCE Department of Human Nutritional Sciences University of Manitoba Winnipeg Copyright © 2011 by Hong Shi TABLE OF CONTENTS ABSTRACT .................................................................................................................... v ACKNOWLEDGEMENTS ......................................................................................... vi LISTOF ABBREVIATIONS ....................................................................................... vii LIST OF TABLES ......................................................................................................... xi LIST OF FIGURES .................................................................................................... xiii INTRODUCTION.......................................................................................................... 1 1. LITERATURE REVIEW .......................................................................................... 1 1-A. Introduction ..................................................................................................... 1 1-A-1. Inflammation – disease link ................................................................. 2 1-A-1-1. Inflammation ................................................................................. 2 1-A-1-2. Chronic inflammation and diseases............................................. 2 1-A-2. Inflammation – eicosanoids link ......................................................... 3 1-A-2-1. Metabolism of arachidonic acid (AA) and eicosanoids ............. 3 1-A-2-1-1. Release of AA from phospholipids ..................................... 5 1-A-2-1-2. Cyclooxygenase (COX) pathway ........................................ 5 1-A-2-1-3. Lipoxygenase (LOX) pathway ............................................ 7 1-A-2-1-4. Cytochrome P450 (CYP) pathway ..................................... 9 1-A-2-2. Generation of hydroxyoctadecdienoic acids (HODEs) from linoleic acid (LA) ...................................................................... 9 1-A-2-3. Physiological effects of eicosanoids .......................................... 12 i 1-A-2-3-1. Physiological effects of eicosanoids on liver ................ 12 1-A-2-3-2. Physiological effects of eicosanoids on kidney ............ 13 1-A-2-4. Regulation of eicosanoids by inflammation ............................ 17 1-A-2-4-1. Up-regulation of eicosanoids in the COX and LOX pathways by inflammation ......................................... 17 1-A-2-4-2. Down-regulation of eicosanoids in the CYP pathway by inflammation ............................................................ 19 1-B. Obesity ........................................................................................................... 21 1-B-1. Obesity and metabolic syndrome ...................................................... 21 1-B-2. Obesity and inflammation ................................................................. 21 1-B-2-1. Hepatic steatosis in obesity ....................................................... 22 1-B-2-1-1. Hepatic steatosis in obesity and inflammation ............ 22 1-B-2-1-2. Eicosanoids and hepatic steatosis in obesity ................ 23 1-B-2-2. Kidney in obesity ....................................................................... 24 1-B-2-2-1. Kidney in obesity and inflammation ............................ 24 1-B-2-2-2. Eicosanoids and kidney in obesity ................................ 25 1-C. Conjugated linoleic acid (CLA) ................................................................... 26 1-C-1. Sources of CLA ................................................................................... 26 1-C-2. Effects of CLA isomers ...................................................................... 27 1-C-2-1. Anti-obesity ................................................................................ 28 1-C-2-2. Anti-diabetes .............................................................................. 28 1-C-2-3. Anti-atherosclerosis ................................................................... 29 ii 1-C-2-4. Anti-inflammation ..................................................................... 30 1-C-2-5. Anti-carcinogenesis ................................................................... 33 1-D. Summary ....................................................................................................... 36 1-E. Hypotheses ..................................................................................................... 37 1-F. Objectives ....................................................................................................... 37 2. MATERIALS AND METHODS ............................................................................. 38 2-1. Animal model and diet ................................................................................... 38 2-2. Lyophilization of liver .................................................................................... 39 2-3. Preparation of tissues for Western blotting .................................................. 42 2-4. Total protein determination ........................................................................... 42 2-5. Western blotting .............................................................................................. 43 2-5-1. Optimization of antibody and protein amount ................................. 43 2-5-2. Protein separation by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) ............................................................. 44 2-5-3. Immunoblotting ................................................................................... 64 2-6. Measurement of eicosanoids ............................................................................ 67 2-6-1. Homogenization and sample treatment............................................. 67 2-6-2. Solid-phase extraction of eicosanoids from tissues ........................... 73 2-6-3. High performance liquid chromatography (HPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS) .... 73 2-7. Statistical analysis ............................................................................................. 77 3. RESULTS ................................................................................................................. 78 iii 3-1. Endogenous levels and in vitro production of eicosanoids in liver .............. 78 3-2. Protein levels of COX1, COX2 and 12/15-LOX in liver ............................... 78 3-3. Endogenous levels and in vitro production of eicosanoids in kidney ........... 84 3-4. Protein levels of enzymes involved in eicosanoid metabolism in kidney ................................................................................................................. 89 4. DISCUSSION ......................................................................................................... 100 4-1. Liver discussion ............................................................................................... 100 4-2. Kidney discussion ........................................................................................... 103 5. CONCLUSION ...................................................................................................... 108 6. LIMITATIONS ....................................................................................................... 109 7. FUTURE RESEARCH .......................................................................................... 110 8. REFERENCES ........................................................................................................ 111 9. APPENDIX ................................................................................................................ A iv ABSTRACT Seventeen wk old male obese Zucker rats were given 0.4% (w/w) conjugated linoleic acid (CLA) isomers for 8 wk to determine effects of specific isomers on multiple eicosanoids in obesity. Liquid-chromatography-mass spectrometry analysis showed that compared to controls, those given t10,c12 CLA had increased liver leukotriene B4 levels, while immunoblotting revealed that rats given either t10,c12 or c9,t11 CLA had lower liver cyclooxygenase-2. In kidney, compared to c9,t11 CLA or controls, t10,c12 CLA increased cyclooxygenase-1, 6-keto-prostaglandin F2α and thromboxane B2 and inhibited the in vitro production of 13-hydroxyoctadecadienoic acid and 5-, 8-, 12- and 15-hydroxyeicosatetraenoic acid. In lean compared to fa/fa rats, endogenous levels and in vitro production of liver and kidney 9- and 13-hydroxyoctadecadienoic acid were elevated. Previous investigations on these tissues revealed that t10,c12 CLA reduced hepatic steatosis, but increased renal damage. How these changes in eicosanoids in response to t10,c12 CLA relate to the previous findings remains to be elucidated. v ACKNOWLEDGMENTS I would like to express my thanks to my supervisor, Dr. Harold Aukema for giving his time, assistance and experience to me. Thank you to my committee members, Dr. Carla Taylor and Dr. Elissavet Kardami for agreeing to be a part of my committee, taking the time to meet. Thank you to Dr. Carla Taylor and Dr. Peter Zahradka for providing the tissues from their research to me and giving
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