File(s) under permanent embargo
The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling
journal contribution
posted on 2018-08-01, 00:00 authored by Gaia Botteri, Laia Salvadó, Anna Gumà, Lee HamiltonLee 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-CarreraOBJECTIVE: 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.
History
Journal
Metabolism: clinical and experimentalVolume
85Pagination
59 - 75Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
eISSN
1532-8600Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2018, Elsevier Inc.Usage metrics
Categories
No categories selectedKeywords
BACE1CREBinsulin resistanceNF-κBpalmitatePGC-1αsAPPβScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismNF-kappa BPGC-1 alphaSAPP betaENDOPLASMIC-RETICULUM STRESSSKELETAL-MUSCLEGENE-TRANSCRIPTIONAMYLOID-BETAHEPATIC GLUCONEOGENESISMITOCHONDRIAL-FUNCTIONFATTY-ACIDSALPHA GENERESISTANCEPGC-1-ALPHA
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC