Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation
| Autor: | Cole M. Haynes, Adolfo Garcia-Ocaña, Misung Kim, Dirk Homann, Bennett Davenport, Mark A. Herman, Liora S. Katz, Jerry E. Chipuk, Lucy Li, Anna M Schulz, Donald K. Scott, Lee B Honig, Anil Kumar |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
NF-E2-Related Factor 2 Recombinant Fusion Proteins Endocrinology Diabetes and Metabolism Transgene Mice Transgenic 030209 endocrinology & metabolism Carbohydrate metabolism Mitochondrial Dynamics Tissue Culture Techniques Mice 03 medical and health sciences Oxygen Consumption 0302 clinical medicine Cell Line Tumor Insulin-Secreting Cells Insulin Secretion Cadaver Internal Medicine Animals Humans Insulin Cell Proliferation Regulation of gene expression Organelle Biogenesis biology Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Chemistry Cell growth Nuclear Proteins Metabolism Rats Cell biology Mice Inbred C57BL Luminescent Proteins Protein Subunits Glucose 030104 developmental biology Islet Studies Gene Expression Regulation Mitochondrial biogenesis Mitogen-activated protein kinase biology.protein RNA Interference Organelle biogenesis Transcription Factors |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db17-0943 |
| Popis: | Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose, a natural mitogen, drives adaptive expansion of β-cell mass by promoting β-cell proliferation. We previously demonstrated that a carbohydrate response element–binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation. ChREBPα increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPα required the presence of ChREBPβ. ChREBPα increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPα-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBPα-augmented β-cell proliferation. Overexpression of Nrf2 was sufficient to drive human β-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for β-cell proliferation that may be exploited for therapeutic β-cell regeneration. |
| Databáze: | OpenAIRE |
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