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Title: The Bace1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling
Author: Botteri, Gaia
Salvadó Serra, Laia
Gumà i Garcia, Anna Maria
Lee Hamilton, D.
Meakin, Paul J.
Montagut, Gemma
Ashford, Michael
Ceperuelo-Mallafré, Victoria
Fernández-Veledo, Sonia
Vendrell, Joan
Calderón Domínguez, María
Serra i Cucurull, Dolors
Herrero Rodríguez, Laura
Pizarro Delgado, Javier
Barroso Fernández, Emma
Palomer Tarridas, Francesc Xavier
Vázquez Carrera, Manuel
Keywords: Insulina
Resistència a la insulina
Reticle endoplasmàtic
Ratolins (Animals de laboratori)
Insulin resistance
Endoplasmic reticulum
Mice (Laboratory animals)
Issue Date: 9-Mar-2018
Publisher: W.B. Saunders
Abstract: Objective -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. Materials/Methods 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. 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  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. Conclusions 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.
Note: Versió postprint del document publicat a:
It is part of: Metabolism-Clinical and Experimental, 2018, vol. 85, p. 59-75
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ISSN: 0026-0495
Appears in Collections:Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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