TY - JOUR
T1 - Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 β-cell survival
AU - Véret, Julien
AU - Coant, Nicolas
AU - Gorshkova, Irina A.
AU - Giussani, Paola
AU - Fradet, Magali
AU - Riccitelli, Elena
AU - Skobeleva, Anastasia
AU - Goya, Jonathan
AU - Kassis, Nadim
AU - Natarajan, Viswanathan
AU - Portha, Bernard
AU - Berdyshev, Evgeny V.
AU - Le Stunff, Hervé
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - (dihydro)Sphingosine-1-phosphate
KW - Cell death
KW - Ceramides
KW - Gluco-lipotoxicity
KW - Pancreatic β cells
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=84868524114&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868524114&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2012.10.003
DO - 10.1016/j.bbalip.2012.10.003
M3 - Article
C2 - 23085009
AN - SCOPUS:84868524114
VL - 1831
SP - 251
EP - 262
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
SN - 1388-1981
IS - 2
ER -