| RRC ID |
21916
|
| 著者 |
Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M.
|
| タイトル |
The Keap1-Nrf2 system prevents onset of diabetes mellitus.
|
| ジャーナル |
Mol Cell Biol
|
| Abstract |
Transcription factor Nrf2 (NF-E2-related factor 2) regulates a broad cytoprotective response to environmental stresses. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown (Keap1flox/-) markedly suppresses the onset of diabetes. When Keap1flox/- mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1flox/- also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im {oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.
|
| 巻・号 |
33(15)
|
| ページ |
2996-3010
|
| 公開日 |
2013-8-1
|
| DOI |
10.1128/MCB.00225-13
|
| PII |
MCB.00225-13
|
| PMID |
23716596
|
| PMC |
PMC3719683
|
| MeSH |
Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Blood Glucose / analysis
Blood Glucose / metabolism
Cell Line
Cytoskeletal Proteins / genetics*
Cytoskeletal Proteins / metabolism
Diabetes Mellitus / genetics*
Diabetes Mellitus / metabolism*
Female
Gene Deletion
Gene Expression Regulation
Gene Knockdown Techniques*
Gluconeogenesis
Insulin / metabolism
Kelch-Like ECH-Associated Protein 1
Male
Mice
Mice, Inbred C57BL
Muscle, Skeletal / metabolism
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Obesity / genetics
Obesity / metabolism
|
| IF |
3.611
|
| 引用数 |
156
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC01386 |
