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

Meakin, Paul J., Mezzapesa, Anna, Benabou, Eva, Haas, Mary E., Bonardo, Bernadette, Grino, Michel, Brunel, Jean-Michel, Desbois-Mouthon, Christèle, Biddinger, Sudha B., Govers, Roland, Ashford, Michael L. J., Peiretti, Franck·2018·Nature Communications
DOI 10.1038/s41467-018-03755-2PMC PMC5880807
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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.

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  • Through additional substrates, BACE1 has been implicated in inflammation, cardiovascular function, glucose homeostasis, and insulin signaling.

    “Through these additional substrates, BACE1 has been implicated in inflammation, cardiovascular function, glucose homeostasis, and insulin signaling”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [18]

    The Introduction implicates BACE1 in glucose homeostasis and insulin signaling, and the Discussion identifies the insulin receptor as a BACE1 substrate. Our copy does not establish the claimed links to inflammation or cardiovascular function through additional BACE1 substrates; the passages have no page numbers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • BACE1 has been implicated in a range of metabolic functions.

    “and BACE1 has been implicated in a range of metabolic functions.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [18]

  • The influence of BACE1 on insulin signaling is in part through negative regulators PTEN and PTP1B, which are found to decrease in response to BACE1 inhibition.

    “The influence of BACE1 on insulin signaling is in part through negative regulators PTEN and PTP1B, which are found to decrease in response to BACE1 inhibition.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [18]

  • BACE1 can reduce the cell surface expression of biologically active insulin receptors via cleavage of its ectodomain, in a glucose-dependent manner.

    “Furthermore, BACE1 can reduce the cell surface expression of biologically active IRs via cleavage of its ectodomain, in a glucose‐dependent manner”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [18]

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Metadata

Authors
Meakin, P. J., Mezzapesa, A., Benabou, E., Haas, M. E., Bonardo, B., Grino, M., Brunel, J.-M., Desbois-Mouthon, C., Biddinger, S. B., Govers, R., Ashford, M. L. J., & Peiretti, F.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-04-03
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-03755-2
PMC
PMC5880807
Cited by
80
References
3
Language
en
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