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Title

Insulin-secreting beta-cell dysfunction induced by human lipoproteins

Authors
Mooser, Vincent
Lenain, Vincent
Herz, Joachim
Nimpf, Johannes
Azhar, Salman
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Published in Journal of Biological Chemistry. 2003, vol. 278, no. 20, p. 18368-18375
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 AnimalsApoptosisBlotting, WesternCaspase 3Caspases/metabolismCell DivisionCell SurvivalCells, CulturedDNA, Complementary/metabolismEnzyme ActivationHumansImmunohistochemistryIn Situ Nick-End LabelingInsulin/metabolismIslets of Langerhans/cytology/metabolism/pathologyLipoproteins/metabolismLipoproteins, LDL/metabolismLipoproteins, VLDL/metabolismMiceMice, Inbred C57BLProtein Structure, TertiaryProtein-Serine-Threonine KinasesProto-Oncogene Proteins/metabolismProto-Oncogene Proteins c-aktReverse Transcriptase Polymerase Chain ReactionSignal TransductionTime Factors
Identifiers
PMID: 12594227
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Article (Published version) (517 Kb) - public document Free access
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Research group Médecine interne générale et pédiatrie ambulatoires (968)
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ROEHRICH, Marc-Estienne Maurice et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins. In: Journal of Biological Chemistry, 2003, vol. 278, n° 20, p. 18368-18375. https://archive-ouverte.unige.ch/unige:86162

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Deposited on : 2016-08-17

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