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

TY - JOUR

T1 - The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

AU - Botteri, Gaia

AU - Salvadó, Laia

AU - Gumà, Anna

AU - Hamilton, D. Lee

AU - Meakin, Paul J.

AU - Montagut , Gemma

AU - Ashford, Michael L. J.

AU - Ceperuelo-Mallafré, Victoria

AU - Fernández-Veledo, Sonia

AU - Vendrell, Joan

AU - Calderón-Dominguez, María

AU - Serra, Dolors

AU - Herrero, Laura

AU - Pizarro, Javier

AU - Barroso, Emma

AU - Palomer, Xavier

AU - Vázquez-Carrera, Manuel

N1 - This study was partly supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2012-30708 and SAF2015-64146-R to MVC, SAF2013-45887-R to LH, SAF2014-52223-C2-1-R to DS, SAF2015-65019-R to SFV and PI14/00228 to JV), the Generalitat de Catalunya (2014SGR-13 to MVC and 2014SGR465 to DS), Diabetes UK Grants (Grant nos. 08/0003681 and 12/0004458 to MLJA), European Union ERDF funds, and the European Foundation for the Study of Diabetes (EFSD)/JanssenRising Star and L’Oréal-UNESCO “For Women in Science” research fellowships to LH. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project (Grant CB07/08/0003 to MVC and CB07/08/0012 to JV). CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 granted to DS). GB was supported by a FPI grant from the Spanish Ministerio de Economía y Competitividad. SFV acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria (FIS) cofinanced by the ERDF. We would like to thank the University of Barcelona’s Language Advisory Service for revising the manuscript.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

KW - BACE1

KW - CREB

KW - NF-κB

KW - PGC-1α

KW - insulin resistance

KW - palmitate

KW - sAPPβ

UR - https://www.scopus.com/pages/publications/85053081687

U2 - 10.1016/j.metabol.2018.03.005

DO - 10.1016/j.metabol.2018.03.005

M3 - Article

C2 - 29526536

SN - 0026-0495

VL - 85

SP - 59

EP - 75

JO - Metabolism

JF - Metabolism

ER -