Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in gluco-lipotoxicity-induced apoptosis of INS-1 β-cells. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Biochemical Journal Année : 2011

Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in gluco-lipotoxicity-induced apoptosis of INS-1 β-cells.

Julien Véret
  • Fonction : Auteur
Nicolas Coant
  • Fonction : Auteur
Evgeny Berdyshev
  • Fonction : Auteur
Anastasia Skobeleva
  • Fonction : Auteur
Nicole Therville
Danielle Bailbé
  • Fonction : Auteur
Irina Gorshkova
  • Fonction : Auteur
Viswanathan Natarajan
  • Fonction : Auteur
Bernard Portha
  • Fonction : Auteur

Résumé

Pancreatic β-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of gluco-lipotoxicity-induced β-cell apoptosis. In INS-1 β-cells, 0.4 mM palmitate with 5 mM glucose increased the levels of dihydrosphingosine and dihydroceramides, two lipid intermediates in the de novo biosynthesis of ceramides, without inducing apoptosis. Increasing glucose concentrations to 30 mM amplified palmitate-induced accumulation of dihydrosphingosine and the formation of (dihydro)-ceramides. Of note, gluco-lipotoxicity specifically induced the formation of 18:0, 22:0 and 24:1 (dihydro)-ceramide molecular species, which was associated with the up-regulation of ceramide synthase 4 (CerS4) levels. Fumonisin-B1, a ceramide synthase inhibitor, partially blocked apoptosis induced by gluco-lipotoxicity. In contrast, apoptosis was potentiated in the presence of D,L-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, an inhibitor of glucosyl-ceramide synthase. Moreover, over-expression of CerS4 amplified ceramide production and apoptosis induced by palmitate with 30 mM glucose whereas down-regulation of CerS4 by siRNA reduced apoptosis. CerS4 also potentiates ceramide accumulation and apoptosis induced by another saturated fatty acid, stearate. Collectively, our results suggest that gluco-lipotoxicity induced β-cell apoptosis through a dual mechanism involving the de novo ceramide biosynthesis and the formation of ceramides with specific N-acyl chain lengths rather than an overall increase of ceramide content.

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Dates et versions

hal-00612967 , version 1 (02-08-2011)

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Julien Véret, Nicolas Coant, Evgeny Berdyshev, Anastasia Skobeleva, Nicole Therville, et al.. Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in gluco-lipotoxicity-induced apoptosis of INS-1 β-cells.. Biochemical Journal, 2011, 438 (1), pp.177-189. ⟨10.1042/BJ20101386⟩. ⟨hal-00612967⟩
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