Reference - Detail
| RRC ID | 76703 |
|---|---|
| Author | Tsuyama T, Sato Y, Yoshizawa T, Matsuoka T, Yamagata K. |
| Title | Hypoxia causes pancreatic β-cell dysfunction and impairs insulin secretion by activating the transcriptional repressor BHLHE40. |
| Journal | EMBO Rep |
| Abstract |
Hypoxia can occur in pancreatic β-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on β-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 β-cells and suppresses insulin secretion. Conversely, BHLHE40 deficiency in hypoxic MIN6 cells or β-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 β-cells was recovered by MAFA re-expression. Collectively, our work identifies BHLHE40 as a key hypoxia-induced transcriptional repressor in β-cells that inhibit insulin secretion by suppressing MAFA expression. |
| Volume | 24(8) |
| Pages | e56227 |
| Published | 2023-8-3 |
| DOI | 10.15252/embr.202256227 |
| PMID | 37341148 |
| PMC | PMC10398664 |
| MeSH | Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Diabetes Mellitus, Type 2* / genetics Diabetes Mellitus, Type 2* / metabolism Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Humans Hypoxia / genetics Hypoxia / metabolism Insulin / metabolism Insulin Secretion Insulin-Secreting Cells* / metabolism Mice Mice, Inbred Strains Pancreas / metabolism |
| IF | 7.497 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 18 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | pCAGGS-HA-Dec1 (mouse) (RDB08473) |