| First Author | Katz LS | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 4423 |
| PubMed ID | 35908073 | Mgi Jnum | J:327368 |
| Mgi Id | MGI:7328065 | Doi | 10.1038/s41467-022-32162-x |
| Citation | Katz LS, et al. (2022) Maladaptive positive feedback production of ChREBPbeta underlies glucotoxic beta-cell failure. Nat Commun 13(1):4423 |
| abstractText | Preservation and expansion of beta-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPbeta) is a nuclear effector of hyperglycemic stress occurring in beta-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPbeta is necessary for adaptive beta-cell expansion in response to metabolic challenges. Conversely, chronic excessive beta-cell-specific overexpression of ChREBPbeta results in loss of beta-cell identity, apoptosis, loss of beta-cell mass, and diabetes. Furthermore, beta-cell "glucolipotoxicity" can be prevented by deletion of ChREBPbeta. Moreover, ChREBPbeta-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPalpha, or by activation of the antioxidant Nrf2 pathway in rodent and human beta-cells. We conclude that ChREBPbeta, whether adaptive or maladaptive, is an important determinant of beta-cell fate and a potential target for the preservation of beta-cell mass in diabetes. |
