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

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, 85, pp. 59-75. https://doi.org/10.1016/j.metabol.2018.03.005

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.

Keywords
BACE1; CREB; insulin resistance; NF-κB; palmitate; PGC-1α; sAPPβ

Notes
Additional co-authors: Xavier Palomer and Manuel Vázquez-Carrera

Journal
Metabolism: Volume 85

• Accepted manuscript