title: Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 β-cell survival.
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.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Véret
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coant
authors.forename: Irina A
authors.initials: IA
authors.lastname: Gorshkova
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
authors.forename: Magali
authors.initials: M
authors.lastname: Fradet
authors.forename: Elena
authors.initials: E
authors.lastname: Riccitelli
authors.forename: Anastasia
authors.initials: A
authors.lastname: Skobeleva
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goya
authors.forename: Nadim
authors.initials: N
authors.lastname: Kassis
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Bernard
authors.initials: B
authors.lastname: Portha
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D017931:DNA Primers; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000235:genetics; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D019308:Palmitic Acid; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D008246:Lysophospholipids; D012333:RNA, Messenger; C060506:sphingosine 1-phosphate; D019308:Palmitic Acid; D013110:Sphingosine