Tenomodulin, serum amyloid A and the serum amyloid A receptor selenoprotein S - implications for metabolic disease
Year: 2010
Type: dissertation
Study design: Observational Study
Abstract: Obesity and obesity-related metabolic diseases are associated with a low-grade inflammation,\nincluding slightly increased serum levels of the acute phase protein serum amyloid A (A-SAA).\nA-SAA is one amongst several adipose tissue (AT) produced proteins suggested to influence\ndevelopment of metabolic diseases. The A-SAA protein may have pro-atherogenic functions, and\nrelease of A-SAA from the AT may contribute to the development of cardiovascular disease.\nFurthermore, 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.\nTo 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 casecontrol\nstudy of coronary heart disease and (4) generated a mouse model with transgenic overexpression of the human SAA1 (hSAA) gene in AT.\nThe 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.\nInflammatory 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\nwhen 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\ndisease.\nIn the hSAA mouse model, hSAA was specifically expressed in AT and plasma levels of hSAA were\nincreased in obese mice. The hSAA protein was found to be co-localized to high-density lipoprotein containing fractions of plasma.\nIn 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.
Author: Maja Olsson
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1557587832