論文 - 詳細
| RRC ID | 75007 |
|---|---|
| 著者 | Bian L, Nguyen VT, Tamaoki J, Endo Y, Dong G, Sato A, Kobayashi M. |
| タイトル | Genetic hyperactivation of Nrf2 causes larval lethality in Keap1a and Keap1b-double-knockout zebrafish. |
| ジャーナル | Redox Biol |
| Abstract |
The Keap1-Nrf2 pathway is an evolutionarily conserved mechanism that protects cells from oxidative stress and electrophiles. Keap1 is a repressor of Nrf2 in normal cellular conditions but also a stress sensor for Nrf2 activation. Interestingly, fish and amphibians have two Keap1s (Keap1a and Keap1b), of which Keap1b is the ortholog of mammalian Keap1. Keap1a, on the other hand, is a gene found only in fish and amphibians, having been lost during the evolution to amniotes. We have previously shown that keap1b-knockout zebrafish have increased Nrf2 activity and reduced response to certain Nrf2-activating compounds but that they grow normally to adulthood. This may be because the remaining keap1a suppresses the hyperactivation of Nrf2, which is responsible for the post-natal lethality of Keap1-knockout mice. In this study, we analyzed keap1a;keap1b-double-knockout zebrafish to test this hypothesis. We found that keap1a;keap1b-double-knockout zebrafish, like Keap1-knockout mice, showed eating defects and were lethal within a week of hatching. Genetic introduction of the Nrf2 mutation rescued both the eating defects and the larval lethality, indicating that Nrf2 hyperactivation is the cause. However, unlike Keap1-knockout mice, keap1a;keap1b-double-knockout zebrafish showed no physical blockage of the food pathway; moreover, the cause of death was not directly related to eating defects. RNA-sequencing analysis revealed that keap1a;keap1b-double-knockout larvae showed extraordinarily high expression of known Nrf2-target genes as well as decreased expression of visual cycle genes. Finally, trigonelline or brusatol partially rescued the lethality of keap1a;keap1b-double-knockout larvae, suggesting that they can serve as an in vivo evaluation system for Nrf2-inhibiting compounds. |
| 巻・号 | 62 |
| ページ | 102673 |
| 公開日 | 2023-6-1 |
| DOI | 10.1016/j.redox.2023.102673 |
| PII | S2213-2317(23)00074-5 |
| PMID | 36934645 |
| PMC | PMC10031532 |
| MeSH | Animals Carrier Proteins / metabolism Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism Larva / genetics Mammals / metabolism Mice Mice, Knockout NF-E2-Related Factor 2* / genetics NF-E2-Related Factor 2* / metabolism Oxidative Stress Zebrafish* / genetics Zebrafish* / metabolism Zebrafish Proteins / genetics Zebrafish Proteins / metabolism |
| IF | 9.986 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | keap1a it302 keap1b it308 |