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A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells

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...

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Autores principales: Cimmino, Ilaria, Lorenzo, Virginia, Fiory, Francesca, Doti, Nunzianna, Ricci, Serena, Cabaro, Serena, Liotti, Antonietta, Vitagliano, Luigi, Longo, Michele, Miele, Claudia, Formisano, Pietro, Beguinot, Francesco, Ruvo, Menotti, Oriente, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641094/
https://www.ncbi.nlm.nih.gov/pubmed/29069751
http://dx.doi.org/10.18632/oncotarget.18286
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author Cimmino, Ilaria
Lorenzo, Virginia
Fiory, Francesca
Doti, Nunzianna
Ricci, Serena
Cabaro, Serena
Liotti, Antonietta
Vitagliano, Luigi
Longo, Michele
Miele, Claudia
Formisano, Pietro
Beguinot, Francesco
Ruvo, Menotti
Oriente, Francesco
author_facet Cimmino, Ilaria
Lorenzo, Virginia
Fiory, Francesca
Doti, Nunzianna
Ricci, Serena
Cabaro, Serena
Liotti, Antonietta
Vitagliano, Luigi
Longo, Michele
Miele, Claudia
Formisano, Pietro
Beguinot, Francesco
Ruvo, Menotti
Oriente, Francesco
author_sort Cimmino, Ilaria
collection PubMed
description 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 (IC(50) = 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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spelling pubmed-56410942017-10-24 A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells Cimmino, Ilaria Lorenzo, Virginia Fiory, Francesca Doti, Nunzianna Ricci, Serena Cabaro, Serena Liotti, Antonietta Vitagliano, Luigi Longo, Michele Miele, Claudia Formisano, Pietro Beguinot, Francesco Ruvo, Menotti Oriente, Francesco Oncotarget Research Paper 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 (IC(50) = 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. Impact Journals LLC 2017-05-30 /pmc/articles/PMC5641094/ /pubmed/29069751 http://dx.doi.org/10.18632/oncotarget.18286 Text en Copyright: © 2017 Cimmino et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Cimmino, Ilaria
Lorenzo, Virginia
Fiory, Francesca
Doti, Nunzianna
Ricci, Serena
Cabaro, Serena
Liotti, Antonietta
Vitagliano, Luigi
Longo, Michele
Miele, Claudia
Formisano, Pietro
Beguinot, Francesco
Ruvo, Menotti
Oriente, Francesco
A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title_full A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title_fullStr A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title_full_unstemmed A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title_short A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
title_sort peptide antagonist of prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641094/
https://www.ncbi.nlm.nih.gov/pubmed/29069751
http://dx.doi.org/10.18632/oncotarget.18286
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