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)

Research output: Contribution to journalArticle

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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

Fingerprint

Amyloid Precursor Protein Secretases
insulin
Insulin Receptor
liver
Liver
Medical problems
glucose
inhibitors
cleavage
Insulin
Glucose
Amyloid beta-Protein Precursor
homeostasis
Liver Neoplasms
Tumors
Protein Isoforms
Homeostasis
enzymes
Plasmas
tumors

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., ... 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
Meakin, Paul ; Mezzapesa, Anna ; Benabou, Eva ; Haas, Mary ; Bonardo, Bernadette ; Grino, Michel ; Brunel, Jean-Michel ; Biddinger, Sudha B. ; Desbois-Mouthon, Christele ; Govers, Roland ; Ashford, Michael L. J. ; Peiretti, Franck. / The beta secretase BACE1 regulates the expression of the insulin receptor in the liver. In: Nature Communications. 2018 ; Vol. 9. pp. 1-14.
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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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Meakin, P, Mezzapesa, A, Benabou, E, Haas, M, Bonardo, B, Grino, M, Brunel, J-M, Biddinger, SB, Desbois-Mouthon, C, Govers, R, Ashford, MLJ & Peiretti, F 2018, 'The beta secretase BACE1 regulates the expression of the insulin receptor in the liver', Nature Communications, vol. 9, 1306, pp. 1-14. https://doi.org/10.1038/s41467-018-03755-2

The beta secretase BACE1 regulates the expression of the insulin receptor in the liver. / Meakin, Paul; Mezzapesa, Anna ; Benabou, Eva; Haas, Mary; Bonardo, Bernadette; Grino, Michel; Brunel, Jean-Michel; Biddinger, Sudha B.; Desbois-Mouthon, Christele; Govers, Roland; Ashford, Michael L. J.; Peiretti, Franck (Lead / Corresponding author).

In: Nature Communications, Vol. 9, 1306, 03.04.2018, p. 1-14.

Research output: Contribution to journalArticle

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T1 - The beta secretase BACE1 regulates the expression of the insulin receptor in the liver

AU - Meakin, Paul

AU - Mezzapesa, Anna

AU - Benabou, Eva

AU - Haas, Mary

AU - Bonardo, Bernadette

AU - Grino, Michel

AU - Brunel, Jean-Michel

AU - Biddinger, Sudha B.

AU - Desbois-Mouthon, Christele

AU - Govers, Roland

AU - Ashford, Michael L. J.

AU - Peiretti, Franck

N1 - he work performed within C2VN was supported by funds from Inserm and Société Francophone du Diabète. The work performed within the Saint-Antoine Research Center was supported by grants from the Institut National du Cancer (INCa-DGOS_5790), GEFLUC and Ligue Contre le Cancer (Comité de Paris). EB is supported by a PhD grant from the Ligue Contre le Cancer. MLJA is funded by Medical Research Council (MR/K003291/1) and British Heart Foundation (PG/15/44/31574).

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N2 - 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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KW - Insulin signalling

KW - Proteases

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KW - Humans

KW - Mice, Inbred C57BL

KW - Glucose/chemistry

KW - Male

KW - Mice, Transgenic

KW - Glycosylation

KW - Aspartic Acid Endopeptidases/metabolism

KW - Amyloid Precursor Protein Secretases/metabolism

KW - Animals

KW - Liver/metabolism

KW - HEK293 Cells

KW - Insulin/metabolism

KW - Protein Domains

KW - Female

KW - Mice

KW - Diabetes Mellitus/metabolism

KW - Receptor, Insulin/metabolism

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