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  • The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells.

The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells.

Diabetologia (2015-03-27)
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
RESUMEN

The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) 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 p66(Shc) was investigated using pancreatic islets from p66 (Shc-/-) mice and in INS-1E cells with knockdown of p66(Shc) or overexpression of wild-type and phosphorylation-defective p66(Shc). Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Palmitate induced a selective increase in p66(Shc) protein expression and phosphorylation on Ser(36) 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 p66(Shc) expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 (Shc-/-) mice and following p66 (Shc) knockdown in INS-1E cells; by contrast, overexpression of p66(Shc), but not that of the phosphorylation-defective p66(Shc) mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66(Shc) were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser(36) and associated with generation of ROS. p66(Shc) protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors. p53-dependent augmentation of p66(Shc) expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

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