Pancreatic β-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of glucolipotoxicity-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, glucolipotoxicity specifically induced the formation of C18:0, C22:0 and C24:1 (dihydro)ceramide molecular species, which was associated with the up-regulation of CerS4 (ceramide synthase 4) levels. Fumonisin-B1, a ceramide synthase inhibitor, partially blocked apoptosis induced by glucolipotoxicity. In contrast, apoptosis was potentiated in the presence of D,L-threo-1-phenyl-2-palmitoylamino-3-morpholinopropan-1-ol, an inhibitor of glucosylceramide synthase. Moreover, overexpression of CerS4 amplified ceramide production and apoptosis induced by palmitate with 30 mM glucose, whereas down-regulation of CerS4 by siRNA (short interfering RNA) reduced apoptosis. CerS4 also potentiates ceramide accumulation and apoptosis induced by another saturated fatty acid: stearate. Collectively, our results suggest that glucolipotoxicity induces β-cell apoptosis through a dual mechanism involving de novo ceramide biosynthesis and the formation of ceramides with specific N-acyl chain lengths rather than an overall increase in ceramide content.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
August 2011
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
July 27 2011
Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 β-cells
Julien Véret;
Julien Véret
*Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France
Search for other works by this author on:
Nicolas Coant;
Nicolas Coant
*Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France
Search for other works by this author on:
Evgeny V. Berdyshev;
Evgeny V. Berdyshev
†Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
Search for other works by this author on:
Anastasia Skobeleva;
Anastasia Skobeleva
†Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
Search for other works by this author on:
Nicole Therville;
Nicole Therville
‡INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
Search for other works by this author on:
Danielle Bailbé;
Danielle Bailbé
*Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France
Search for other works by this author on:
Irina Gorshkova;
Irina Gorshkova
†Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
Search for other works by this author on:
Viswanathan Natarajan;
Viswanathan Natarajan
†Department of Medicine, Section of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
Search for other works by this author on:
Bernard Portha;
Bernard Portha
*Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France
Search for other works by this author on:
Hervé Le Stunff
Hervé Le Stunff
1
*Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie et Pathologie du Pancréas Endocrine, Unité BFA, CNRS EAC 4413, Paris, France
1To whom correspondence should be addressed (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
September 01 2010
Revision Received:
April 06 2011
Accepted:
May 19 2011
Accepted Manuscript online:
May 19 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (1): 177–189.
Article history
Received:
September 01 2010
Revision Received:
April 06 2011
Accepted:
May 19 2011
Accepted Manuscript online:
May 19 2011
Citation
Julien Véret, Nicolas Coant, Evgeny V. Berdyshev, Anastasia Skobeleva, Nicole Therville, Danielle Bailbé, Irina Gorshkova, Viswanathan Natarajan, Bernard Portha, Hervé Le Stunff; Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 β-cells. Biochem J 15 August 2011; 438 (1): 177–189. doi: https://doi.org/10.1042/BJ20101386
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |