| First Author | Tsuyama T | Year | 2023 |
| Journal | EMBO Rep | Volume | 24 |
| Issue | 8 | Pages | e56227 |
| PubMed ID | 37341148 | Mgi Jnum | J:338218 |
| Mgi Id | MGI:7510244 | Doi | 10.15252/embr.202256227 |
| Citation | Tsuyama T, et al. (2023) Hypoxia causes pancreatic beta-cell dysfunction and impairs insulin secretion by activating the transcriptional repressor BHLHE40. EMBO Rep :e56227 |
| abstractText | Hypoxia can occur in pancreatic beta-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on beta-cell function, the associated mechanisms are largely unknown. Here, we show that the transcriptional repressor basic helix-loop-helix family member e40 (BHLHE40) is highly induced in hypoxic mouse and human beta-cells and suppresses insulin secretion. Conversely, BHLHE40 deficiency in hypoxic MIN6 cells or beta-cells of ob/ob mice reverses defects in insulin secretion. Mechanistically, BHLHE40 represses the expression of Mafa, encoding the transcription factor musculoaponeurotic fibrosarcoma oncogene family A (MAFA), by attenuating the binding of pancreas/duodenum homeobox protein 1 (PDX1) to its enhancer region. Impaired insulin secretion in hypoxic beta-cells was recovered by MAFA re-expression. Collectively, our work identifies BHLHE40 as a key hypoxia-induced transcriptional repressor in beta-cells that inhibit insulin secretion by suppressing MAFA expression. |
