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Involvement of 4E-BP1 in the protection induced by HDLs on pancreatic beta-cells.

Authors
  • Pétremand, Jannick1
  • Bulat, Natasa
  • Butty, Anne-Christine
  • Poussin, Carine
  • Rütti, Sabine
  • Au, Karin
  • Ghosh, Sujoy
  • Mooser, Vincent
  • Thorens, Bernard
  • Yang, Jiang-Yan
  • Widmann, Christian
  • Waeber, Gérard
  • 1 Department of Physiology, Lausanne University, 1005 Lausanne, Switzerland. , (Switzerland)
Type
Published Article
Journal
Molecular Endocrinology
Publisher
The Endocrine Society
Publication Date
Oct 01, 2009
Volume
23
Issue
10
Pages
1572–1586
Identifiers
DOI: 10.1210/me.2008-0448
PMID: 19574449
Source
Medline
Language
English
License
Unknown

Abstract

High-density lipoproteins (HDLs) protect pancreatic beta-cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. However, the mechanisms by which HDLs protect beta-cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in beta-cells subjected to apoptotic stimuli. The transcript encoding 4E-binding protein (4E-BP)1 was up-regulated by serum starvation, and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypophosphorylated state but it loses this ability when hyperphosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL-1beta, and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced beta-cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect beta-cells by blocking 4E-BP1 protein expression, but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by endoplasmic reticulum stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect beta-cells through modulation of 4E-BP1 depending on the type of stress stimuli.

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