The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

Annalisa Natalicchio, Federica Tortosa, Rossella Labarbuta, Giuseppina Biondi, Nicola Marrano, Emanuele Carchia, Anna Leonardini, Angelo Cignarelli, Marco Bugliani, Piero Marchetti, Gian Paolo Fadini, Marco Giorgio, Angelo Avogaro, Sebastio Perrini, Luigi Laviola, Francesco Giorgino

Research output: Contribution to journalArticle

Abstract

Aims/hypothesis: The role of the redox adaptor protein p66Shc as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. Methods: The effects of the FA palmitate on p66Shc expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66Shc expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66Shc was investigated using pancreatic islets from p66Shc−/− mice and in INS-1E cells with knockdown of p66Shc or overexpression of wild-type and phosphorylation-defective p66Shc. Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Results: Palmitate induced a selective increase in p66Shc protein expression and phosphorylation on Ser36 and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66Shc expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66Shc−/− mice and following p66Shc knockdown in INS-1E cells; by contrast, overexpression of p66Shc, but not that of the phosphorylation-defective p66Shc mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66Shc were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser36 and associated with generation of ROS. p66Shc protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors. Conclusions/interpretation: p53-dependent augmentation of p66Shc expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

Original languageEnglish
Pages (from-to)1260-1271
Number of pages12
JournalDiabetologia
Volume58
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

Keywords

  • Apoptosis
  • Beta cell
  • Exendin-4
  • JNK
  • p53
  • p66<sup>Shc</sup>
  • Palmitic acid
  • Pancreatic islet

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Natalicchio, A., Tortosa, F., Labarbuta, R., Biondi, G., Marrano, N., Carchia, E., Leonardini, A., Cignarelli, A., Bugliani, M., Marchetti, P., Fadini, G. P., Giorgio, M., Avogaro, A., Perrini, S., Laviola, L., & Giorgino, F. (2015). The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells. Diabetologia, 58(6), 1260-1271. https://doi.org/10.1007/s00125-015-3563-2