The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus
The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus
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DOI：
10.1128/mcb.00225-13
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发表时间：
2013-08-01
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Uruno, Akira;Furusawa, Yuki;Yamamoto, Masayuki
转录因子Nrf2 （nf - e2相关因子2）调节细胞对环境胁迫的广泛保护反应。Keap1 （Kelch-like ECH-associated protein 1）是cullin3泛素E3连接酶的衔接蛋白，负调控Nrf2。虽然Keap1-Nrf2系统在氧化应激反应和代谢中发挥重要作用，但Nrf2在糖尿病预防中的作用尚不清楚。本研究表明，通过Keap1基因亚型敲低（Keap1(flox/-)）激活Nrf2信号可以显著抑制糖尿病的发生。当Keap1（flox/-）小鼠与糖尿病db/db小鼠杂交时，通过改善胰岛素分泌和胰岛素抵抗，血糖水平降低。Keap1（flox/-）也能预防高热量饮食引起的糖尿病。口服Nrf2诱导剂cddo - m{齐墩果酸1-[2-氰-3,12-二氧齐墩果酸-1,9(11)-二烯-28-油基]咪唑}也能减轻db/db小鼠的糖尿病。Nrf2诱导改变代谢组织中抗氧化、能量消耗和糖异生相关基因的表达。因此，Keap1-Nrf2系统是预防糖尿病发病的关键靶点。
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 (Keap1(flox/-)) markedly suppresses the onset of diabetes. When Keap1(flox/-) mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1(flox/-) 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.