Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 β-cell survival

Julien Véret, Nicolas Coant, Irina A. Gorshkova, Paola Giussani, Magali Fradet, Elena Riccitelli, Anastasia Skobeleva, Jonathan Goya, Nadim Kassis, Viswanathan Natarajan, Bernard Portha, Evgeny V. Berdyshev, Hervé Le Stunff

Research output: Contribution to journalArticlepeer-review

Abstract

Sphingoid base-1-phosphates represent a very low portion of the sphingolipid pool but are potent bioactive lipids in mammals. This study was undertaken to determine whether these lipids are produced in palmitate-treated pancreatic β cells and what role they play in palmitate-induced β cell apoptosis. Our lipidomic analysis revealed that palmitate at low and high glucose supplementation increased (dihydro)sphingosine-1-phosphate levels in INS-1 β cells. This increase was associated with an increase in sphingosine kinase 1 (SphK1) mRNA and protein levels. Over-expression of SphK1 in INS-1 cells potentiated palmitate-induced accumulation of dihydrosphingosine-1- phosphate. N,N-dimethyl-sphingosine, a potent inhibitor of SphK, potentiated β-cell apoptosis induced by palmitate whereas over-expression of SphK1 significantly reduced apoptosis induced by palmitate with high glucose. Endoplasmic reticulum (ER)-targeted SphK1 also partially inhibited apoptosis induced by palmitate. Inhibition of INS-1 apoptosis by over-expressed SphK1 was independent of sphingosine-1-phosphate receptors but was associated with a decreased formation of pro-apoptotic ceramides induced by gluco-lipotoxicity. Moreover, over-expression of SphK1 counteracted the defect in the ER-to-Golgi transport of proteins that contribute to the ceramide-dependent ER stress observed during gluco-lipotoxicity. In conclusion, our results suggest that activation of palmitate-induced SphK1-mediated sphingoid base-1-phosphate formation in the ER of β cells plays a protective role against palmitate-induced ceramide-dependent apoptotic β cell death.

Original languageEnglish
Pages (from-to)251-262
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1831
Issue number2
DOIs
Publication statusPublished - Feb 2013

Keywords

  • (dihydro)Sphingosine-1-phosphate
  • Cell death
  • Ceramides
  • Gluco-lipotoxicity
  • Pancreatic β cells
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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