Author, as appears in the article.: Botteri, Gaia; Salvado, Laia; Guma, Anna; Hamilton, D Lee; Meakin, Paul J; Montagut, Gemma; Ashford, Michael L J; Ceperuelo-Mallafre, Victoria; Fernandez-Veledo, Sonia; Vendrell, Joan; Calderon-Dominguez, Maria; Serra, Dolors; Herrero, Laura; Pizarro, Javier; Barroso, Emma; Palomer, Xavier; Vazquez-Carrera, Manuel
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; Signal transduction; Sappβ; Sapp?; Sapp beta; Resistance; Pgc-1α; Pgc-1?; Pgc-1-alpha; Pgc-1 alpha; Palmitic acid; Palmitate; Nf-κb; Nf-kappa b; Nf-?b; Muscle, skeletal; Muscle fibers, skeletal; Mitochondrial-function; Mice; Male; Insulin resistance; Insulin; Inflammation; Humans; Hepatic gluconeogenesis; Gene-transcription; Fatty-acids; Endoplasmic-reticulum stress; Endoplasmic reticulum stress; Creb; Cells, cultured; Cell line; Bace1 protein, mouse; Bace1; Aspartic acid endopeptidases; Animals; Amyloid-beta; Amyloid precursor protein secretases; 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: victoria.ceperuelo@urv.cat; sonia.fernandez@urv.cat; jvortega@iispv.cat
Record's date: 2025-02-08
Paper version: info:eu-repo/semantics/acceptedVersion
Link to the original source: https://www.metabolismjournal.com/article/S0026-0495(18)30071-4/fulltext
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Paper original source: Metabolism Clinical And Experimental. 85 59-75
APA: Botteri, Gaia; Salvado, Laia; Guma, Anna; Hamilton, D Lee; Meakin, Paul J; Montagut, Gemma; Ashford, Michael L J; Ceperuelo-Mallafre, Victoria; Fernan (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
Article's DOI: 10.1016/j.metabol.2018.03.005
Entity: Universitat Rovira i Virgili
Journal publication year: 2018
Publication Type: Journal Publications
Repositori URV