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.
Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 β-cell survival / J. Véret, N. Coant, I.A. Gorshkova, P. Giussani, M. Fradet, E. Riccitelli, A. Skobeleva, J. Goya, N. Kassis, V. Natarajan, B. Portha, E.V. Berdyshev, H. Le Stunff. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS. - ISSN 1388-1981. - 1831:2(2013), pp. 251-262.
|Titolo:||Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 β-cell survival|
|Parole Chiave:||(dihydro)Sphingosine-1-phosphate; Cell death; Ceramides; Gluco-lipotoxicity; Pancreatic β cells; Type 2 diabetes|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||2013|
|Data ahead of print / Data di stampa:||17-ott-2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bbalip.2012.10.003|
|Appare nelle tipologie:||01 - Articolo su periodico|