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

Gaia Botteri, Laia Salvadó, Anna Gumà, D. Lee Hamilton, Paul J. Meakin, Gemma Montagut , Michael L. J. Ashford, Victoria Ceperuelo-Mallafré, Sonia Fernández-Veledo, Joan Vendrell, María Calderón-Dominguez, Dolors Serra, Laura Herrero, Javier Pizarro, Emma Barroso, Xavier Palomer, Manuel Vázquez-Carrera (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)59-75
Number of pages17
JournalMetabolism
Volume85
Early online date9 Mar 2018
DOIs
Publication statusPublished - Aug 2018

Keywords

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

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    Botteri, G., Salvadó, L., Gumà, A., Hamilton, D. L., Meakin, P. J., Montagut , G., Ashford, M. L. J., Ceperuelo-Mallafré, V., Fernández-Veledo, S., Vendrell, J., Calderón-Dominguez, M., Serra, D., Herrero, L., Pizarro, J., Barroso, E., Palomer, X., & Vázquez-Carrera, M. (2018). The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism, 85, 59-75. https://doi.org/10.1016/j.metabol.2018.03.005