Author, as appears in the article.: Botteri G; SalvadoL; Gumà A; Lee Hamilton D; Meakin PJ; Montagut G; Ashford MLJ; Ceperuelo-Mallafré V; Fernández-Veledo S; Vendrell J; Calderón-Dominguez M; Serra D; Herrero L; Pizarro J; Barroso E; Palomer X; Vazquez-Carrera M
Department: Bioquímica i Biotecnologia Medicina i Cirurgia Ciències Mèdiques Bàsiques
URV's Author/s: Ceperuelo Mallafré, Maria Victoria / Fernandez Veledo, Sonia / Vendrell Ortega, Juan José
Keywords: Skeletal-muscle Sapp? Sapp beta Resistance Pgc-1? Pgc-1-alpha Pgc-1 alpha Palmitate Nf-kappa b Nf-?b Mitochondrial-function Insulin resistance Hepatic gluconeogenesis Gene-transcription Fatty-acids Endoplasmic-reticulum stress Creb Bace1 Amyloid-beta Alpha gene pgc-1? palmitate nf-?b insulin resistance creb bace1
Abstract: ?-secretase/?-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 APP? (sAPP?), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells.Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/-mice and mice treated with sAPP? and adipose tissue and plasma from obese and type 2 diabetic patients.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 ? Co-activator 1? (PGC-1?) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1? down-regulation, and fatty acid oxidation were mimicked by soluble APP? 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-1? mRNA levels and by an increase in sAPP? plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPP? administration to mice reduced PGC-1? levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.Collectively, these findings indicate that the BACE1 product sAPP? is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.Copyright © 2018 Elsevier Inc. All rights reserved.
licence for use: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 0026-0495
Author's mail: sonia.fernandez@urv.cat victoria.ceperuelo@urv.cat juanjose.vendrell@urv.cat
Author identifier: 0000-0003-2906-3788 0000-0002-4460-9761 0000-0002-6994-6115
Record's date: 2023-11-11
Papper version: info:eu-repo/semantics/acceptedVersion
Papper original source: Metabolism Clinical And Experimental. 85 59-75
APA: Botteri G; SalvadoL; Gumà A; Lee Hamilton D; Meakin PJ; Montagut G; Ashford MLJ; Ceperuelo-Mallafré V; Fernández-Veledo S; Vendrell J; Calderón-Doming (2018). The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling.. Metabolism Clinical And Experimental, 85(), 59-75. DOI: 10.1016/j.metabol.2018.03.005
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Entity: Universitat Rovira i Virgili
Journal publication year: 2018
Publication Type: Journal Publications
Repositori URV