Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/26841
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dc.contributor.authorBotteri, Gaiaen_UK
dc.contributor.authorSalvado, Laiaen_UK
dc.contributor.authorGuma, Annaen_UK
dc.contributor.authorHamilton, David Leeen_UK
dc.contributor.authorMeakin, Paul Jen_UK
dc.contributor.authorMontagut, Gemmaen_UK
dc.contributor.authorAshford, Michael L Jen_UK
dc.contributor.authorCeperuelo-Mallafre, Victoriaen_UK
dc.contributor.authorFernandez-Veledo, Soniaen_UK
dc.contributor.authorVendrell, Joanen_UK
dc.contributor.authorCalderon-Dominguez, Mariaen_UK
dc.contributor.authorSerra, Dolorsen_UK
dc.contributor.authorHerrero, Lauraen_UK
dc.contributor.authorPizarro, Javieren_UK
dc.contributor.authorBarroso, Emmaen_UK
dc.date.accessioned2018-03-21T23:32:14Z-
dc.date.available2018-03-21T23:32:14Z-
dc.date.issued2018-08en_UK
dc.identifier.urihttp://hdl.handle.net/1893/26841-
dc.description.abstractObjective  β-secretase/β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPβ (sAPPβ), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells.  Materials/Methods  Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1−/−mice and mice treated with sAPPβ and adipose tissue and plasma from obese and type 2 diabetic patients.  Results  We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator-Activated Receptor γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.  Conclusions  Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.en_UK
dc.language.isoenen_UK
dc.publisherElsevieren_UK
dc.relationBotteri G, Salvado L, Guma A, Hamilton DL, Meakin PJ, Montagut G, Ashford MLJ, Ceperuelo-Mallafre V, Fernandez-Veledo S, Vendrell J, Calderon-Dominguez M, Serra D, Herrero L, Pizarro J & Barroso E (2018) The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism, 85, pp. 59-75. https://doi.org/10.1016/j.metabol.2018.03.005en_UK
dc.rightsThis item has been embargoed for a period. During the embargo please use the Request a Copy feature at the foot of the Repository record to request a copy directly from the author. You can only request a copy if you wish to use this work for your own research or private study. Accepted refereed manuscript of: Botteri G, Salvado L, Guma A, Hamilton DL, Meakin PJ, Montagut G, Ashford MLJ, Ceperuelo-Mallafre V, Fernandez-Veledo S, Vendrell J, Calderon-Dominguez M, Serra D, Herrero L, Pizarro J & Barroso E (2018) The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism, 85, pp. 59-75. DOI: https://doi.org/10.1016/j.metabol.2018.03.005 © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/en_UK
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_UK
dc.subjectBACE1en_UK
dc.subjectCREBen_UK
dc.subjectinsulin resistanceen_UK
dc.subjectNF-κBen_UK
dc.subjectpalmitateen_UK
dc.subjectPGC-1αen_UK
dc.subjectsAPPβen_UK
dc.titleThe BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signalingen_UK
dc.typeJournal Articleen_UK
dc.rights.embargoreason[Botteri et al 2018.pdf] Publisher requires embargo of 12 months after formal publication.en_UK
dc.identifier.doi10.1016/j.metabol.2018.03.005en_UK
dc.identifier.pmid29526536en_UK
dc.citation.jtitleMetabolismen_UK
dc.citation.issn1532-8600en_UK
dc.citation.issn0026-0495en_UK
dc.citation.volume85en_UK
dc.citation.spage59en_UK
dc.citation.epage75en_UK
dc.citation.publicationstatusPublisheden_UK
dc.citation.peerreviewedRefereeden_UK
dc.type.statusAM - Accepted Manuscripten_UK
dc.author.emaild.l.hamilton@stir.ac.uken_UK
dc.citation.date08/03/2018en_UK
dc.description.notesAdditional co-authors: Xavier Palomer and Manuel Vázquez-Carreraen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationSporten_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversitat Rovira i Virgilien_UK
dc.contributor.affiliationUniversitat Rovira i Virgilien_UK
dc.contributor.affiliationUniversitat Rovira i Virgilien_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.contributor.affiliationUniversitat de Barcelonaen_UK
dc.identifier.isiWOS:000454746400007en_UK
dc.identifier.scopusid2-s2.0-85053081687en_UK
dc.identifier.wtid494604en_UK
dc.contributor.orcid0000-0002-5620-4788en_UK
dc.date.accepted2018-03-05en_UK
dc.date.filedepositdate2018-03-21en_UK
Appears in Collections:Faculty of Health Sciences and Sport Journal Articles

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