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

Paul Meakin, Anna Mezzapesa, Eva Benabou, Mary Haas, Bernadette Bonardo, Michel Grino, Jean-Michel Brunel, Sudha B. Biddinger, Christele Desbois-Mouthon, Roland Govers, Michael L. J. Ashford, Franck Peiretti (Lead / Corresponding author)

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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.
Original languageEnglish
Article number1306
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 3 Apr 2018

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Keywords

  • Hepatocellular carcinoma
  • Insulin signalling
  • Proteases
  • Type 2 diabetes
  • Neoplasms/metabolism
  • Signal Transduction
  • Antigens, CD/metabolism
  • Humans
  • Mice, Inbred C57BL
  • Glucose/chemistry
  • Male
  • Mice, Transgenic
  • Glycosylation
  • Aspartic Acid Endopeptidases/metabolism
  • Amyloid Precursor Protein Secretases/metabolism
  • Animals
  • Liver/metabolism
  • HEK293 Cells
  • Insulin/metabolism
  • Protein Domains
  • Female
  • Mice
  • Diabetes Mellitus/metabolism
  • Receptor, Insulin/metabolism

Cite this

Meakin, P., Mezzapesa, A., Benabou, E., Haas, M., Bonardo, B., Grino, M., Brunel, J-M., Biddinger, S. B., Desbois-Mouthon, C., Govers, R., Ashford, M. L. J., & Peiretti, F. (2018). The beta secretase BACE1 regulates the expression of the insulin receptor in the liver. Nature Communications, 9, 1-14. [1306]. https://doi.org/10.1038/s41467-018-03755-2