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Tenomodulin, Serum Amyloid a and the Serum Amyloid a Receptor Selenoprotein S – Implications for Metabolic Disease

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Tenomodulin, Serum Amyloid a and the Serum Amyloid a Receptor Selenoprotein S – Implications for Metabolic Disease Tenomodulin, serum amyloid A and the serum amyloid A receptor selenoprotein S – implications for metabolic disease Academic dissertation Maja Olsson Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine Sahlgrenska Academy University of Gothenburg Sweden 2010 © Maja Olsson, 2010 Published papers have been reprinted with permission from the copyright holders. ISBN 978-91-628-8042-2 Printed by Intellecta Infolog AB, Göteborg, 2010 2 ABSTRACT Obesity and obesity-related metabolic diseases are associated with a low-grade inflammation, including slightly increased serum levels of the acute phase protein serum amyloid A (A-SAA). A-SAA is one amongst several adipose tissue (AT) produced proteins suggested to influence development of metabolic diseases. The A- SAA protein may have pro-atherogenic functions, and release of A-SAA from the AT may contribute to the development of cardiovascular disease. Furthermore, A-SAA is functionally linked to insulin resistance via one of its receptors, selenoprotein S (SELS). The tenomodulin (TNMD) gene is expressed in adipose tissue, but its role in obesity is unclear. The overall aim of this thesis was to increase our understanding of how TNMD, A-SAA and SELS relate to obesity and obesity-associated metabolic diseases. An additional aim was to establish a mouse model mirroring the human A-SAA production in AT. To achieve these goals, we (1) investigated TNMD gene expression in human AT by DNA microarray and real-time PCR analysis; (2) analyzed serum levels of A-SAA in a cohort with a wide range in body mass index and metabolic parameters; (3) analyzed SELS gene expression and genotyped three SELS polymorphisms, previously associated with serum levels of inflammatory markers, in a case-control study of coronary heart disease and (4) generated a mouse model with transgenic over- expression of the human SAA1 (hSAA) gene in AT. The TNMD gene was highly expressed in human AT, with a higher expression in obese compared to lean subjects. Furthermore, TNMD gene expression was down- regulated during diet-induced weight loss. These data suggest that TNMD plays a role in the adipose tissue. Inflammatory markers and measures of glycemic control were strongly associated with serum levels of A-SAA. The strongest associations were found in women, and serum levels of A-SAA were associated with adipocyte size in women only. These data suggest that sex-specific factors have to be considered when analyzing serum levels of A-SAA in relation to metabolic disease. Gene expression of SELS in AT was associated with measures of obesity. Furthermore, genetic variants in the SELS gene were associated with serum levels of glucose, measures of insulin resistance and blood pressure. These findings suggest that SELS plays a role in the development of metabolic disease. In the hSAA mouse model, hSAA was specifically expressed in AT and plasma levels of hSAA were increased in obese mice. The hSAA protein was found to be co-localized to high-density lipoprotein containing fractions of plasma. In conclusion, the results of this thesis suggest that TNMD, A-SAA and SELS have metabolic effects that should be further explored. The established hSAA transgenic mouse model opens the possibility to further explore the effects of AT-derived A-SAA on cardiovascular disease. 3 TABLE OF CONTENTS ABSTRACT............................................................................................................................... 3 TABLE OF CONTENTS........................................................................................................... 4 LIST OF PAPERS...................................................................................................................... 5 1 INTRODUCTION................................................................................................................... 7 1.1 Obesity ............................................................................................................................. 7 1.2 Insulin Resistance............................................................................................................. 8 1.3 The Metabolic Syndrome ................................................................................................. 9 1.4 Atherosclerosis................................................................................................................. 9 1.5 Adipose Tissue ................................................................................................................. 9 1.5.1 Adipokines .............................................................................................................. 10 1.6 Serum amyloid A (SAA)................................................................................................ 12 1.6.1 Early studies of the SAA protein............................................................................. 12 1.6.2 The SAA gene family.............................................................................................. 12 1.6.3 SAA levels in the circulation .................................................................................. 12 1.6.4 SAA expression in adipose tissue and association with circulating SAA levels .... 13 1.6.5 Suggested roles of A-SAA ...................................................................................... 13 1.6.6 The putative SAA receptor selenoprotein S (SELS)............................................... 14 2 AIMS..................................................................................................................................... 16 3 STUDY COHORTS AND METHODOLOGICAL CONSIDERATIONS .......................... 17 3.1 Subjects .......................................................................................................................... 17 3.1.1 The Depot Study...................................................................................................... 17 3.1.2 The Very Low Calorie Diet Study (VLCD) I and II............................................... 17 3.1.3 The Swedish Obese Subjects (SOS) Sib Pair Study ............................................... 18 3.1.4 The “Umeå cohort” ................................................................................................. 18 3.1.5 The INTERGENE Study......................................................................................... 18 3.2 Ribonucleic acid (RNA) extraction................................................................................ 19 3.3 Gene expression analysis ............................................................................................... 19 3.3.1 Real-time PCR analysis using TaqMan chemistry.................................................. 19 3.3.2 Gene expression analysis using GeneChip technology........................................... 20 3.4 Genetic variation in the human genome......................................................................... 21 3.4.1 Genotyping using TaqMan SNP technology........................................................... 22 3.5. Animal Experiments...................................................................................................... 22 3.5.1 The use of transgenic mice...................................................................................... 22 3.5.2 Transgenic mice over-expressing human SAA in adipose tissue ........................... 23 4 RESULTS AND DISCUSSION ........................................................................................... 25 4.1 Paper I ............................................................................................................................ 25 4.2 Paper II ........................................................................................................................... 27 4.3 Paper III.......................................................................................................................... 29 4.4 Paper IV.......................................................................................................................... 31 4.5 A final note regarding SAA ........................................................................................... 33 5 SUMMARY .......................................................................................................................... 35 6 ACKNOWLEDGEMENTS .................................................................................................. 36 7 REFERENCES...................................................................................................................... 38 4 LIST OF PAPERS This thesis is based upon the following papers and manuscripts: I Tenomodulin is highly expressed in adipose tissue, increased in obesity, and down-regulated during diet-indued weight loss. Saiki A1, Olsson M1, Jernås M, Gummesson A, McTernan PG, Andersson J, Jacobson P, Sjöholm K, Olsson B, Yamamura S, Walley A, Froguel P, Carlsson B, Sjöström L, Svensson P-A, Carlsson LMS. J Clin Endocrinol Metab. 2009;94(10):3987-94. II Association of serum amyloid A levels with adipocyte size and serum levels of adipokines: differences between men and women. Sjöholm K, Lundgren M, Olsson M, Eriksson JW. Cytokine. 2009;48(3):260-6 III Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors. Olsson M, Olsson B, Jacobson P, Thelle DS, Björkegren J, Walley A, Froguel P, Carlsson LMS, Sjöholm
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