دورية أكاديمية
Genetic dissection of serum vaspin highlights its causal role in lipid metabolism.
| العنوان: | Genetic dissection of serum vaspin highlights its causal role in lipid metabolism. |
|---|---|
| المؤلفون: | Breitfeld J; Department of Medicine, University of Leipzig, Leipzig, Germany., Horn K; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE Research Center, University of Leipzig, Leipzig, Germany., Le Duc D; Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany., Velluva A; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany., Marzi C; Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.; German Research Center for Environmental Health, Institute of Epidemiology II, Helmholtz Center Munich, Neuherberg, Germany.; German Center for Diabetic Research (DZD e.V.), Neuherberg, Germany., Grallert H; Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.; German Research Center for Environmental Health, Institute of Epidemiology II, Helmholtz Center Munich, Neuherberg, Germany.; German Center for Diabetic Research (DZD e.V.), Neuherberg, Germany., Friedrich N; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research), Greifswald, Germany., Pietzner M; Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.; DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany., Völker U; DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.; Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany., Völzke H; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany., Ahlqvist E; Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden., Aly DM; Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden., Tuomi T; Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden.; Institute for Molecular Medicine Finland, Helsinki;, Division of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.; Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland.; Folkhälsan Research Center, Helsinki, Finland., Baber R; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany., Kratzsch J; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany., Thiery J; Christian-Albrechts-University Kiel, University Kiel, Kiel, Germany., Isermann B; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany., Loeffler M; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE Research Center, University of Leipzig, Leipzig, Germany., Klöting N; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Blüher M; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Stumvoll M; Department of Medicine, University of Leipzig, Leipzig, Germany.; Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.; German Center for Diabetic Research (DZD e.V.), Neuherberg, Germany., Heiker JT; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Tönjes A; Department of Medicine, University of Leipzig, Leipzig, Germany., Scholz M; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE Research Center, University of Leipzig, Leipzig, Germany., Kovacs P; Department of Medicine, University of Leipzig, Leipzig, Germany. |
| المصدر: | Obesity (Silver Spring, Md.) [Obesity (Silver Spring)] 2023 Nov; Vol. 31 (11), pp. 2862-2874. Date of Electronic Publication: 2023 Sep 26. |
| نوع المنشور: | Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101264860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1930-739X (Electronic) Linking ISSN: 19307381 NLM ISO Abbreviation: Obesity (Silver Spring) Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2013- : Malden, MA : John Wiley & Sons Original Publication: Silver Spring, MD : NAASO, the Obesity Society, c2006- |
| مواضيع طبية MeSH: | Lipid Metabolism*/genetics , Serpins*/blood , Serpins*/genetics, Animals ; Mice ; Adipokines/metabolism ; Genome-Wide Association Study ; Obesity/metabolism ; Triglycerides ; Humans |
| مستخلص: | Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10 -8 , explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism. (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.) |
| References: | Hida K, Wada J, Eguchi J, et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci U S A. 2005;102(30):10610-10615. doi:10.1073/pnas.0504703102. Blüher M. Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine. 2012;41(2):176-182. doi:10.1007/s12020-011-9572-0. Youn BS, Klöting N, Kratzsch J, et al. Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes. 2008;57(2):372-377. doi:10.2337/db07-1045. Klöting N, Kovacs P, Kern M, et al. Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects. Diabetologia. 2011;54(7):1819-1823. doi:10.1007/s00125-011-2137-1. Dimova R, Tankova T. The role of vaspin in the development of metabolic and glucose tolerance disorders and atherosclerosis. Biomed Res Int. 2015;1-7. doi:10.1155/2015/823481. Heiker JT, Klöting N, Kovacs P, et al. Vaspin inhibits kallikrein 7 by serpin mechanism. Cell Mol Life Sci. 2013;70(14):2569-2583. doi:10.1007/s00018-013-1258-8. Skytt A, Stromqvist M, Egelrud T. Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme. Biochem Biophys Res Commun. 1995;211(2):586-589. Nakatsuka A, Wada J, Iseda I, et al. Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex. Diabetes. 2012;61(11):2823-2832. doi:10.2337/db12-0232. Nakatsuka A, Wada J, Iseda I, et al. Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex. Circ Res. 2013;112(5):771-780. doi:10.1161/CIRCRESAHA.111.300049. Jung CH, Lee WJ, Hwang JY, et al. Vaspin protects vascular endothelial cells against free fatty acid-induced apoptosis through a phosphatidylinositol 3-kinase/Akt pathway. Biochem Biophys Res Commun. 2011;413(2):264-269. doi:10.1016/j.bbrc.2011.08.083. Sun N, Wang H, Wang L. Vaspin alleviates dysfuction of endothelial progenitor cells induced by high glucose via PI3K/Akt/eNOS pathway. Int J Clin Exp Pathol. 2015;8(1):482-489. Kempf K, Rose B, Illig T, et al. Vaspin (SERPINA12) genotypes and risk of type 2 diabetes: results from the MONICA/KORA studies. Exp Clin Endocrinol Diabetes. 2010;118(3):184-189. Breitfeld J, Tönjes A, Böttcher Y, et al. Genetic variation in the vaspin gene affects circulating serum vaspin concentrations. Int J Obes (Lond). 2013;37(6):861-866. doi:10.1038/ijo.2012.133. Teshigawara S, Wada J, Hida K, et al. Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. J Clin Endocrinol Metab. 2012;97(7):7-E1207. doi:10.1210/jc.2011-3297. Tönjes A, Koriath M, Schleinitz D, et al. Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of sorbs. Hum Mol Genet. 2009;18(23):4662-4668. doi:10.1093/hmg/ddp423. Wichmann HE, Gieger C, Illig T. KORA-gen - resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen. 2005;67(Suppl 1):S26-30. doi:10.1055/s-2005-858226. Rathmann W, Strassburger K, Heier M, et al. Incidence of type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study. Diabet Med. 2009;26(12):1212-1219. doi:10.1111/j.1464-5491.2009.02863.x. Isomaa B, Forsen B, Lahti K, et al. A family history of diabetes is associated with reduced physical fitness in the prevalence, prediction and prevention of diabetes (PPP)-Botnia study. Diabetologia. 2010;53(8):1709-1713. doi:10.1007/s00125-010-1776-y. Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331-1336. doi:10.1126/science.1142358. Scholz M, Henger S, Beutner F, et al. Cohort profile: the Leipzig research Center for Civilization Diseases-Heart Study (LIFE-heart). Int J Epidemiol. 2020;49(5):1439-1440h. doi:10.1093/ije/dyaa075. Loeffler M, Engel C, Ahnert P, et al. The LIFE-adult-study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany. BMC Public Health. 2015;15:15691. doi:10.1186/s12889-015-1983-z. Wua J, Wang H-M, Li J, Men X-L. The research applications of db/db mouse. Sheng Li Ke Xue Jin Zhan. 2013;44(1):12-18. Ulbricht D, Pippel J, Schultz S, Meier R, Sträter N, Heiker JT. A unique serpin P1' glutamate and a conserved β-sheet C arginine are key residues for activity, protease recognition and stability of serpinA12 (vaspin). Biochem J. 2015;470(3):357-367. doi:10.1042/BJ20150643. Zieger K, Weiner J, Kunath A, et al. Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo. Cell Mol Life Sci. 2018;75(4):727-742. doi:10.1007/s00018-017-2658-y. Võsa U, Claringbould A, Westra H-J, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021;53(9):1300-1310. doi:10.1038/s41588-021-00913-z. Caron B, Patin E, Rotival M, et al. Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes. Genome Med. 2022;14(1):28. doi:10.1186/s13073-022-01032-y. Gudjonsson A, Gudmundsdottir V, Axelsson GT, et al. A genome-wide association study of serum proteins reveals shared loci with common diseases. Nat Commun. 2022;13(1):480. doi:10.1038/s41467-021-27850-z. Breitfeld J, Wiele N, Gutsmann B, et al. Circulating Adipokine VASPIN is associated with serum lipid profiles in humans. Lipids. 2019;54(4):203-210. doi:10.1002/lipd.12139. Tarabeih N, Kalinkovich A, Shalata A, Livshits G. Circulating levels of visceral adipose tissue-derived serine protease inhibitor (Vaspin) appear as a marker of musculoskeletal pain disability. Diagnostics (Basel). 2020;10:1-16. doi:10.3390/diagnostics10100797. von Loeffelholz C, Möhlig M, Arafat AM, et al. Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans. Eur J Endocrinol. 2010;162(3):507-513. doi:10.1530/EJE-09-0737. Choi SH, Kwak SH, Lee Y, et al. Plasma vaspin concentrations are elevated in metabolic syndromein men and are correlated with coronary atherosclerosis in women. Clin Endocrinol (Oxf). 2011;75:628-635. Wada J. Vaspin: a novel serpin with insulin-sensitizing effects. Expert Opin Investig Drugs. 2008;17(3):327-333. doi:10.1517/13543784.17.3.327. Rapöhn I, Elias I, Weiner J, et al. Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse. Front Endocrinol (Lausanne). 2023;141146454;14:1-9. doi:10.3389/fendo.2023.1146454. Tagliabracci VS, Wiley SE, Guo X, et al. A single kinase generates the majority of the secreted Phosphoproteome. Cell. 2015;161(7):1619-1632. doi:10.1016/j.cell.2015.05.028. Bae J-H, Song D-K, Im S-S. Regulation of IGFBP-1 in metabolic diseases. J Lifestyle Med. 2013;3(2):73-79. Pietzner M, Wheeler E, Carrasco-Zanini J, et al. Mapping the proteo-genomic convergence of human diseases. Science. 2021;374(6569):eabj1541. doi:10.1126/science.abj1541. |
| المشرفين على المادة: | 0 (Adipokines) 0 (Serpins) 0 (Triglycerides) 0 (SERPINA12 protein, human) |
| تواريخ الأحداث: | Date Created: 20230927 Date Completed: 20231101 Latest Revision: 20231101 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1002/oby.23882 |
| PMID: | 37752728 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1930-739X |
|---|---|
| DOI: | 10.1002/oby.23882 |