|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: Clinical and Experimental.|
|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.|
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|Notes:||Additional co-authors: Xavier Palomer and Manuel Vázquez-Carrera|
|Botteri et al 2018.pdf||12.77 MB||Adobe PDF||Under Embargo until 2019-03-09 Request a copy|
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