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Insulin-secreting beta-cell dysfunction induced by human lipoproteins

Contributors

Roehrich, Marc-Estienne Maurice; Mooser, Vincent; Lenain, Vincent; Herz, Joachim; Nimpf, Johannes; Azhar, Salman; Bideau Sar, Martine; Capponi, Alessandro Mario; Nicod, Pascal; Haefliger, Jacques-Antoine; Waeber, Gérard

Published in

The Journal of biological chemistry, vol. 278, no. 20, p. 18368-18375

Publication date

2003

Abstract

Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDL-induced apoptosis of beta-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.

Keywords

  • Animals
  • Apoptosis
  • Blotting, Western
  • Caspase 3
  • Caspases/metabolism
  • Cell Division
  • Cell Survival
  • Cells, Cultured
  • DNA, Complementary/metabolism
  • Enzyme Activation
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Insulin/metabolism
  • Islets of Langerhans/cytology/metabolism/pathology
  • Lipoproteins/metabolism
  • Lipoproteins, LDL/metabolism
  • Lipoproteins, VLDL/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-akt
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time Factors

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

ROEHRICH, Marc-Estienne Maurice et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins. In: The Journal of biological chemistry, 2003, vol. 278, n° 20, p. 18368–18375. doi: 10.1074/jbc.M300102200

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

0021-9258
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289downloads

Technical informations

Creation

16/08/2016 10:56:00

First validation

16/08/2016 10:56:00

Update

15/03/2023 00:38:13

Status update

15/03/2023 00:38:13

Last indexation

31/10/2024 04:12:36
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