The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
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DOI：
10.1038/nchembio.1069
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发表时间：
2012-11-01
影响因子：
14.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Zhan, Yan-yan;Chen, Yan;Wu, Qiao
肝激酶B1（LKB 1）通过调节能量传感器激酶AMP激活的蛋白激酶（AMPK）的活性，在调节能量稳态中发挥重要作用。然而，LKB 1功能的调节仍然知之甚少。在这里，我们证明了孤儿核受体Nur 77结合和隔离LKB 1在细胞核中，从而减弱AMPK激活。这种Nur 77功能被化合物2-[2，3，4-三甲氧基-6-（1-辛酰基）苯基]乙酸乙酯（TMPA）拮抗，其以高亲和力和在特定位点与Nur 77相互作用。Nur 77的TMPA结合导致LKB 1释放并穿梭至细胞质以磷酸化AMPK α。此外，TMPA有效地降低血糖和减轻II型db/db和高脂饮食和链脲佐菌素诱导的糖尿病小鼠的胰岛素抵抗，但在Nur 77基因敲除的糖尿病同窝仔中没有。这项研究获得了对LKB 1-AMPK轴调节的机制理解，并暗示Nur 77是设计和开发治疗代谢性疾病的治疗药物的新的和可行的靶点。
Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPK alpha. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet-and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.