Title | Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Katz, LS, Brill, G, Zhang, P, Kumar, A, Baumel-Alterzon, S, Honig, LB, Gómez-Banoy, N, Karakose, E, Tanase, M, Doridot, L, Alvarsson, A, Davenport, B, Wang, P, Lambertini, L, Stanley, SA, Homann, D, Stewart, AF, Lo, JC, Herman, MA, Garcia-Ocana, A, Scott, DK |
Journal | Nat Commun |
Volume | 13 |
Issue | 1 |
Pagination | 4423 |
Date Published | 2022 Jul 30 |
ISSN | 2041-1723 |
Keywords | Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Feedback, Glucose, Humans, Insulin-Secreting Cells, Nuclear Proteins |
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. |
DOI | 10.1038/s41467-022-32162-x |
Alternate Journal | Nat Commun |
PubMed ID | 35908073 |
PubMed Central ID | PMC9339008 |
Grant List | R01DK126450 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01AG026518 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) / R01 DK114338 / DK / NIDDK NIH HHS / United States R01DK105015 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / 18-25 / / Charles H. Revson Foundation / R01DK100425 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01DK129196 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01NS097184 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / 2-2007-24 / / Friends United for Juvenile Diabetes Research / R01 DK108905 / DK / NIDDK NIH HHS / United States R01DK116873 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01DK124461 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01DK108905 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01DK130300 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / 1-17-ACE-31 / / American Diabetes Association (ADA) / R01DK12140 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01DK125285 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / R01AI093637 / / Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID) / T32 DK007792 / DK / NIDDK NIH HHS / United States |