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

Liora S. Katz, Gabriel Brill, Pili Zhang, Anil Kumar, Sharon Baumel-Alterzon, Lee B. Honig, Nicolás Gómez-Banoy, Esra Karakose, Marius Tanase, Ludivine Doridot, Alexandra Alvarsson, Bennett Davenport, Peng Wang, Luca Lambertini, Sarah A. Stanley, Dirk Homann, Andrew F. Stewart, James C. Lo, Mark A. Herman, Adolfo Garcia-Ocaña and Donald K. Scott ()
Additional contact information
Liora S. Katz: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Gabriel Brill: Stony Brook University
Pili Zhang: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Anil Kumar: Radiobiology building, Room 151
Sharon Baumel-Alterzon: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Lee B. Honig: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Nicolás Gómez-Banoy: Weill Cornell Medicine
Esra Karakose: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Marius Tanase: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Ludivine Doridot: Université de Paris, INSERM, CNRS
Alexandra Alvarsson: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Bennett Davenport: University of Colorado
Peng Wang: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Luca Lambertini: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Sarah A. Stanley: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Dirk Homann: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Andrew F. Stewart: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
James C. Lo: Weill Cornell Medicine
Mark A. Herman: Duke University Medical Center
Adolfo Garcia-Ocaña: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Donald K. Scott: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32162-x

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