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

  • Gaia Botteri
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
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  • Laia Salvadó
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
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  • Anna Gumà
    Affiliations
    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain
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  • D. Lee Hamilton
    Affiliations
    Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
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  • Paul J. Meakin
    Affiliations
    Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
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  • Gemma Montagut
    Affiliations
    Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
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  • Michael L.J. Ashford
    Affiliations
    Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
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  • Victoria Ceperuelo-Mallafré
    Affiliations
    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
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  • Sonia Fernández-Veledo
    Affiliations
    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
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  • Joan Vendrell
    Affiliations
    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
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  • María Calderón-Dominguez
    Affiliations
    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Barcelona, Spain
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  • Dolors Serra
    Affiliations
    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Barcelona, Spain
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  • Laura Herrero
    Affiliations
    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Barcelona, Spain
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  • Javier Pizarro
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
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  • Emma Barroso
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
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  • Xavier Palomer
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
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  • Manuel Vázquez-Carrera
    Correspondence
    Corresponding author at: Unitat de Farmacologia, Facultat de Farmàcia, Avinguda Joan XXIII 27-31, E-08028 Barcelona, Spain.
    Affiliations
    Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain

    Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain

    Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain

    Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain
    Search for articles by this author

      Highlights

      • BACE1 inhibition prevents palmitate-induced ER stress, inflammation, and insulin resistance in myotubes.
      • BACE1 expression and plasma sAPPβ levels are increased in type 2 diabetic patients.
      • sAPPβ administration to mice induces ER stress, inflammation and reduces PGC-1α in skeletal muscle.
      • The BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle.

      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

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