Insulin-secreting beta-cell dysfunction induced by human lipoproteins

Article Article scientifique Article Insulin-secreting beta-cell dysfunction induced by human lipoproteins eng 2003 author Roehrich Marc-Estienne Maurice 90904 author Mooser Vincent author Lenain Vincent author Herz Joachim author Nimpf Johannes author Azhar Salman author Bideau Sar Martine 57989 author Capponi Alessandro Mario 24743 author Nicod Pascal author Haefliger Jacques-Antoine author Waeber Gérard 18368-18375 10.1074/jbc.M300102200 12594227 0021-9258 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. 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 Dewey 613 Dewey 616 56 Département de médecine 221 64 Département de santé et médecine communautaires 22A false 958 Médecine interne générale et pédiatrie ambulatoires 968 The Journal of biological chemistry 278 20 e420cf5a-2727-47a7-90f1-54147039a316 Article (Published version) Public Insulin-secreting beta-cell dysfunction induced by human lipoproteins..pdf 529829 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires

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Insulin-secreting beta-cell dysfunction induced by human lipoproteins	The Journal of biological chemistry			2003	462	253

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Roehrich, Marc-Estienne Maurice