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 - Funding Information:
D.K.S., R01DK108905, R01DK114338, R01DK130300; J.C.L., R01DK12140; A.F.S., R01DK116873, R01DK125285, R01DK129196; A.G.-O., R01DK125285, R01DK105015, R01DK126450; A.A., Charles H. Revson Foundation (grant no. 18-25), Sweden-America Foundation (Ernst O Eks fond), Swedish Society for Medical Research (SSMF); S.S., American Diabetes Association Pathway to Stop Diabetes Grant ADA #1-17-ACE-31, R01NS097184, OT2OD024912, and R01DK124461, Department of Defense (W81XWH-20-1-0345, W81XWH-20-1-0156); D.H., R01AG026518 and R01AI093637, Juvenile Diabetes Research Foundation Career Development Award 2-2007-240; (B.D.) T32 DK007792; MAH, R01DK100425. We thank the Boston Nutrition Obesity Research Center for generation of mice. We thank the Flow Cytometery, Microscopy, Mouse Genetics and Gene Targeting, the Biorepository and Pathology Cores of Icahn School of Medicine at Mount Sinai. We also thank the Human Islet and Adenovirus Core of the Einstein-Mount Sinai Diabetes Research Center (DK-020541) for generation of adenoviruses and islet transplantation services. We thank Pedro Herrera and Daniel Oropeza for useful discussions.
Funding Information:
D.K.S., R01DK108905, R01DK114338, R01DK130300; J.C.L., R01DK12140; A.F.S., R01DK116873, R01DK125285, R01DK129196; A.G.-O., R01DK125285, R01DK105015, R01DK126450; A.A., Charles H. Revson Foundation (grant no. 18-25), Sweden-America Foundation (Ernst O Eks fond), Swedish Society for Medical Research (SSMF); S.S., American Diabetes Association Pathway to Stop Diabetes Grant ADA #1-17-ACE-31, R01NS097184, OT2OD024912, and R01DK124461, Department of Defense (W81XWH-20-1-0345, W81XWH-20-1-0156); D.H., R01AG026518 and R01AI093637, Juvenile Diabetes Research Foundation Career Development Award 2-2007-240; (B.D.) T32 DK007792; MAH, R01DK100425. We thank the Boston Nutrition Obesity Research Center for generation of mice. We thank the Flow Cytometery, Microscopy, Mouse Genetics and Gene Targeting, the Biorepository and Pathology Cores of Icahn School of Medicine at Mount Sinai. We also thank the Human Islet and Adenovirus Core of the Einstein-Mount Sinai Diabetes Research Center (DK-020541) for generation of adenoviruses and islet transplantation services. We thank Pedro Herrera and Daniel Oropeza for useful discussions.
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 -