Maladaptive Positive Feedback Production of ChREBPβ Underlies Glucotoxic β-Cell Failure

Authors

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
Donald K Scott

Publication Date

7-30-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-32162-x

PMID

35908073

PMCID

PMC9339008

PubMedCentral® Posted Date

7-30-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

no

Keywords

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Feedback, Glucose, Humans, Insulin-Secreting Cells, Nuclear Proteins, Carbohydrates, Diabetes, Mechanisms of disease, Nuclear transport

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.

Comments

This article has been corrected. See Nat Commun. 2022 Sep 27;13:5681.

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