期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1831, 期 2, 页码 251-262出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2012.10.003
关键词
(dihydro)Sphingosine-1-phosphate; Ceramides; Type 2 diabetes; Giuco-lipotoxicity; Cell death; Pancreatic beta cells
资金
- Centre National de la Recherche Scientifique (CNRS)
- Agence Nationale de la Recherche [ANR-06-JCJC-0040]
- French Ministry of Higher Education (Physiology and Physiopathology Doctoral School) [394]
- Universite Paris Diderot
- French Society of Nutrition (SFN)
- University of Milan PUR
- Agence Nationale de la Recherche (ANR) [ANR-06-JCJC-0040] Funding Source: Agence Nationale de la Recherche (ANR)
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 beta cells and what role they play in palmitate-induced beta cell apoptosis. Our lipidomic analysis revealed that palmitate at low and high glucose supplementation increased (dihydro)sphingosine-1-phosphate levels in INS-1 beta cells. This increase was associated with an increase in sphingosine kinase 1 (SphI(I) 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 beta-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-l-phosphate receptors but was associated with a decreased formation of pro-apoptotic ceramides induced by gluco-lipotoxicity. Moreover, overexpression 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-l-phosphate formation in the ER of beta cells plays a protective role against palmitate-induced ceramide-dependent apoptotic beta cell death. (C) 2012 Elsevier B.V. All rights reserved.
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