The beta secretase BACE1 regulates the expression of insulin receptor in the liver

Paul J. Meakin, Anna Mezzapesa, Eva Benabou, Mary E. Haas, Bernadette Bonardo, Michel Grino, Jean-Michel Brunel, Christèle Desbois-Mouthon, Sudha B. Biddinger, Roland Govers, Michael L. J. Ashford and Franck Peiretti ()
Additional contact information
Paul J. Meakin: Ninewells Hospital & Medical School
Anna Mezzapesa: Aix Marseille Univ, INSERM, INRA, C2VN
Eva Benabou: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center
Mary E. Haas: Boston Children’s Hospital
Bernadette Bonardo: Aix Marseille Univ, INSERM, INRA, C2VN
Michel Grino: Aix Marseille Univ, INSERM, INRA, C2VN
Jean-Michel Brunel: Aix Marseille Univ, INSERM, CNRS, CRCM, Institut Paoli Calmettes
Christèle Desbois-Mouthon: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center
Sudha B. Biddinger: Boston Children’s Hospital
Roland Govers: Aix Marseille Univ, INSERM, INRA, C2VN
Michael L. J. Ashford: Ninewells Hospital & Medical School
Franck Peiretti: Aix Marseille Univ, INSERM, INRA, C2VN

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.

Date: 2018
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DOI: 10.1038/s41467-018-03755-2

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