The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling.

Identifier:  imarina:5132425

Handle: https://hdl.handle.net/20.500.11797/imarina5132425

Authors:  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

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.