Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation
| العنوان: | Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation |
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| المؤلفون: | Colin de Haar, Maryam Rakhshandehroo, Robert J. van Eijkeren, Tanit L. Gabriel, Johannes M. F. G. Aerts, Marianne Boes, Sanne M.W. Gijzel, Marco van Eijk, Eric Kalkhoven, Nicole Hamers, Henk S. Schipper, Maria J. Ferraz |
| المساهمون: | Medical Biochemistry, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| المصدر: | Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 1864(8), 1157. Elsevier Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids, 1864, 8, pp. 1157-1167 BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1864(8), 1157-1167. Elsevier Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 1864(8), 1157-1167. ELSEVIER SCIENCE BV Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids, 1864, 1157-1167 |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell signaling, Ceramide, Adipose tissue, Cell Communication, Lymphocyte Activation, Glucosylceramides, Cell Line, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, Journal Article, Humans, Antigen-presenting cell, Molecular Biology, Antigen Presentation, biology, Ugcg, B4Galt6, B4Galt5, Cell Biology, Lipids, Coculture Techniques, Cell biology, 030104 developmental biology, chemistry, Aminosugar, 030220 oncology & carcinogenesis, CD1D, biology.protein, iNKT cell, Cytokines, Natural Killer T-Cells, Insulin Resistance, Cell activation |
| الوصف: | Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes. |
| وصف الملف: | image/pdf; application/pdf |
| اللغة: | English |
| تدمد: | 1388-1981 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1141db17bbdc36ea1dd059c3f82fe81f https://dspace.library.uu.nl/handle/1874/390173 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1141db17bbdc36ea1dd059c3f82fe81f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13881981 |
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