Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Maryam Rakhshandehroo, Robert J. van Eijkeren, Tanit L. Gabriel, Colin de Haar, Sanne M.W. Gijzel, Nicole Hamers, Maria J. Ferraz, Johannes M.F.G. Aerts, Henk S. Schipper, Marco van Eijk, Marianne Boes, Eric Kalkhoven*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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. β-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 (IFNγ and IL4 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.

Original languageEnglish
Pages (from-to)1157-1167
Number of pages11
JournalBiochimica et Biophysica Acta-Molecular and Cell Biology of Lipids
Volume1864
Issue number8
Early online date30 Apr 2019
DOIs
Publication statusPublished - 1 Aug 2019

Keywords

  • Adipocytes
  • B4Galt5
  • B4Galt6
  • Glucosylceramides
  • iNKT cell
  • Ugcg

Fingerprint

Dive into the research topics of 'Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation'. Together they form a unique fingerprint.

Cite this