|Appears in Collections:||Faculty of Health Sciences and Sport Journal Articles|
|Peer Review Status:||Refereed|
|Title:||The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling|
Hamilton, David Lee
Meakin, Paul J
Ashford, Michael L J
|Citation:||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. https://doi.org/10.1016/j.metabol.2018.03.005|
|Abstract:||Objective 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.|
|Rights:||This 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/|
|Notes:||Additional co-authors: Xavier Palomer and Manuel Vázquez-Carrera|
|Botteri et al 2018.pdf||Fulltext - Accepted Version||12.83 MB||Adobe PDF||View/Open|
This item is protected by original copyright
A file in this item is licensed under a Creative Commons License
Items in the Repository are protected by copyright, with all rights reserved, unless otherwise indicated.
If you believe that any material held in STORRE infringes copyright, please contact firstname.lastname@example.org providing details and we will remove the Work from public display in STORRE and investigate your claim.