Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 07 2022
30 07 2022
Historique:
received:
16
12
2021
accepted:
18
07
2022
entrez:
30
7
2022
pubmed:
31
7
2022
medline:
3
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35908073
doi: 10.1038/s41467-022-32162-x
pii: 10.1038/s41467-022-32162-x
pmc: PMC9339008
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Nuclear Proteins
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4423Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK124461
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121140
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116873
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK100425
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007792
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121844
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108905
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105015
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114338
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097184
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI093637
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK129196
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130300
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK126450
Pays : United States
Organisme : NIH HHS
ID : OT2 OD024912
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125285
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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