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Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure

Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat di...

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Autores principales: Katz, Liora S., Brill, Gabriel, Zhang, Pili, Kumar, Anil, Baumel-Alterzon, Sharon, Honig, Lee B., Gómez-Banoy, Nicolás, Karakose, Esra, Tanase, Marius, Doridot, Ludivine, Alvarsson, Alexandra, Davenport, Bennett, Wang, Peng, Lambertini, Luca, Stanley, Sarah A., Homann, Dirk, Stewart, Andrew F., Lo, James C., Herman, Mark A., Garcia-Ocaña, Adolfo, Scott, Donald K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339008/
https://www.ncbi.nlm.nih.gov/pubmed/35908073
http://dx.doi.org/10.1038/s41467-022-32162-x
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author Katz, Liora S.
Brill, Gabriel
Zhang, Pili
Kumar, Anil
Baumel-Alterzon, Sharon
Honig, Lee B.
Gómez-Banoy, Nicolás
Karakose, Esra
Tanase, Marius
Doridot, Ludivine
Alvarsson, Alexandra
Davenport, Bennett
Wang, Peng
Lambertini, Luca
Stanley, Sarah A.
Homann, Dirk
Stewart, Andrew F.
Lo, James C.
Herman, Mark A.
Garcia-Ocaña, Adolfo
Scott, Donald K.
author_facet Katz, Liora S.
Brill, Gabriel
Zhang, Pili
Kumar, Anil
Baumel-Alterzon, Sharon
Honig, Lee B.
Gómez-Banoy, Nicolás
Karakose, Esra
Tanase, Marius
Doridot, Ludivine
Alvarsson, Alexandra
Davenport, Bennett
Wang, Peng
Lambertini, Luca
Stanley, Sarah A.
Homann, Dirk
Stewart, Andrew F.
Lo, James C.
Herman, Mark A.
Garcia-Ocaña, Adolfo
Scott, Donald K.
author_sort Katz, Liora S.
collection PubMed
description Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell “glucolipotoxicity” can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human β-cells. We conclude that ChREBPβ, whether adaptive or maladaptive, is an important determinant of β-cell fate and a potential target for the preservation of β-cell mass in diabetes.
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spelling pubmed-93390082022-08-01 Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure Katz, Liora S. Brill, Gabriel Zhang, Pili Kumar, Anil Baumel-Alterzon, Sharon Honig, Lee B. Gómez-Banoy, Nicolás Karakose, Esra Tanase, Marius Doridot, Ludivine Alvarsson, Alexandra Davenport, Bennett Wang, Peng Lambertini, Luca Stanley, Sarah A. Homann, Dirk Stewart, Andrew F. Lo, James C. Herman, Mark A. Garcia-Ocaña, Adolfo Scott, Donald K. Nat Commun Article Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell “glucolipotoxicity” can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human β-cells. We conclude that ChREBPβ, whether adaptive or maladaptive, is an important determinant of β-cell fate and a potential target for the preservation of β-cell mass in diabetes. Nature Publishing Group UK 2022-07-30 /pmc/articles/PMC9339008/ /pubmed/35908073 http://dx.doi.org/10.1038/s41467-022-32162-x Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access 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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Katz, Liora S.
Brill, Gabriel
Zhang, Pili
Kumar, Anil
Baumel-Alterzon, Sharon
Honig, Lee B.
Gómez-Banoy, Nicolás
Karakose, Esra
Tanase, Marius
Doridot, Ludivine
Alvarsson, Alexandra
Davenport, Bennett
Wang, Peng
Lambertini, Luca
Stanley, Sarah A.
Homann, Dirk
Stewart, Andrew F.
Lo, James C.
Herman, Mark A.
Garcia-Ocaña, Adolfo
Scott, Donald K.
Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title_full Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title_fullStr Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title_full_unstemmed Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title_short Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
title_sort maladaptive positive feedback production of chrebpβ underlies glucotoxic β-cell failure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339008/
https://www.ncbi.nlm.nih.gov/pubmed/35908073
http://dx.doi.org/10.1038/s41467-022-32162-x
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