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

Author

Listed:
  • 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
    Alpenglow Biosciences, Inc.)

  • 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
    Baylor College of Medicine)

  • 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)

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.

Suggested Citation

  • 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, 2022. "Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32162-x
    DOI: 10.1038/s41467-022-32162-x
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    References listed on IDEAS

    as
    1. Mark A. Herman & Odile D. Peroni & Jorge Villoria & Michael R. Schön & Nada A. Abumrad & Matthias Blüher & Samuel Klein & Barbara B. Kahn, 2012. "A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism," Nature, Nature, vol. 484(7394), pages 333-338, April.
    2. Huan Wang & Aaron Bender & Peng Wang & Esra Karakose & William B. Inabnet & Steven K. Libutti & Andrew Arnold & Luca Lambertini & Micheal Stang & Herbert Chen & Yumi Kasai & Milind Mahajan & Yayoi Kin, 2017. "Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

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