TY - JOUR
T1 - Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
AU - Katz, Liora S.
AU - Brill, Gabriel
AU - Zhang, Pili
AU - Kumar, Anil
AU - Baumel-Alterzon, Sharon
AU - Honig, Lee B.
AU - Gómez-Banoy, Nicolás
AU - Karakose, Esra
AU - Tanase, Marius
AU - Doridot, Ludivine
AU - Alvarsson, Alexandra
AU - Davenport, Bennett
AU - Wang, Peng
AU - Lambertini, Luca
AU - Stanley, Sarah A.
AU - Homann, Dirk
AU - Stewart, Andrew F.
AU - Lo, James C.
AU - Herman, Mark A.
AU - Garcia-Ocaña, Adolfo
AU - Scott, Donald K.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135146244&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-32162-x
DO - 10.1038/s41467-022-32162-x
M3 - Article
C2 - 35908073
AN - SCOPUS:85135146244
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4423
ER -