A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
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Ilaria Cimmino1, Virginia Lorenzo2, Francesca Fiory1, Nunzianna Doti2, Serena Ricci1, Serena Cabaro1, Antonietta Liotti1, Luigi Vitagliano2, Michele Longo1, Claudia Miele1, Pietro Formisano1, Francesco Beguinot1, Menotti Ruvo2 and Francesco Oriente1
1Department of Translational Medicine, Federico II University of Naples and URT “Genomic of Diabetes” of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy
2Institute of Biostructure and Bioimaging, National Research Council and Interuniversity Research Centre on Bioactive Peptides, Naples, Italy
Francesco Oriente, email: [email protected]
Keywords: ceramide, Prep1, p160, Prep1(54-72) peptide, insulin signalling
Received: February 15, 2017 Accepted: May 03, 2017 Published: May 30, 2017
Prep1 is a homeodomain transcription factor belonging to the TALE protein family. Its overexpression affects glucose metabolism in several tissues. In particular, in skeletal muscle tissue the interaction of Prep1 with its cofactor p160 impairs GLUT4 expression and glucose uptake.
In this study, we show that ceramides (C2cer), a class of lipids antagonizing insulin signalling, increase the levels of Prep1 and p160 in a dose and time-dependent fashion in L6 cells and induce their association by 80%. We find that C2cer exposure inhibits insulin receptor, IRS1 and Akt phosphorylation and reduces insulin-stimulated glycogen content and glucose uptake by 1.3- and 2.1-fold, respectively. The synthetic Prep1(54-72) peptide, mimicking the Prep1 region involved in the interaction with p160, reduces in vitro Prep1-p160 binding in a dose-dependent way (IC50 = 0.20μM). In C2cer-treated L6 cells, 10μM Prep1(54-72) restores insulin signalling impaired by ceramide treatment. Prep1 overexpressing L6 cells display similar metabolic alterations observed in ceramide-treated L6 cells and the presence of Prep1(54-72) mitigates these events. All these findings suggest that disruption of the Prep1/p160 molecular interaction enhances insulin sensitivity impaired by ceramides in skeletal muscle cells and indicate this complex as an important target for type 2 diabetes.
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