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

doi:10.1038/s41467-018-03755-2

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 journal › Article › peer-review

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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 language	English
Article number	1306
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-03755-2
Publication status	Published - 3 Apr 2018

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

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-03755-2Licence: CC BY

Final Published Version
© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 1.66 MBLicence: CC BY

BACE1 and Endothelial Dysfunction in Diabetes (Project Grant scheme)
Ashford, M. (Investigator) & Khan, F. (Investigator)
British Heart Foundation
1/10/15 → 30/09/18
Project: Research
Targeting the Aspartic Protease BACE1 for Inhibition in Order to Increase Hypothalamic Leptin Sensitivity and Reverse Obesity
Ashford, M. (Investigator)
Medical Research Council
1/01/13 → 31/12/15
Project: Research

Ashford, Michael
- Diabetes Endocrinology and Reproductive Biology - Professor (Teaching and Research)
Person: Academic

Cite this

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title = "The beta secretase BACE1 regulates the expression of the insulin receptor in the liver",

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.",

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",

author = "Paul Meakin and Anna Mezzapesa and Eva Benabou and Mary Haas and Bernadette Bonardo and Michel Grino and Jean-Michel Brunel and Biddinger, {Sudha B.} and Christele Desbois-Mouthon and Roland Govers and Ashford, {Michael L. J.} and Franck Peiretti",

note = "he work performed within C2VN was supported by funds from Inserm and Soci{\'e}t{\'e} Francophone du Diab{\`e}te. 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 (Comit{\'e} 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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doi = "10.1038/s41467-018-03755-2",

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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).

PY - 2018/4/3

Y1 - 2018/4/3

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.

AB - 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.

KW - Hepatocellular carcinoma

KW - Insulin signalling

KW - Proteases

KW - Type 2 diabetes

KW - Neoplasms/metabolism

KW - Signal Transduction

KW - Antigens, CD/metabolism

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

U2 - 10.1038/s41467-018-03755-2

DO - 10.1038/s41467-018-03755-2

M3 - Article

C2 - 29610518

SN - 2041-1723

VL - 9

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

M1 - 1306

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Projects

BACE1 and Endothelial Dysfunction in Diabetes (Project Grant scheme)

Targeting the Aspartic Protease BACE1 for Inhibition in Order to Increase Hypothalamic Leptin Sensitivity and Reverse Obesity

Profiles

Ashford, Michael

Cite this