State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Nat Chem Biol. 2012 Nov;8(11):897-904. doi: 10.1038/nchembio.1069. Epub 2012 Sep 16.
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 AMPKα. 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.
肝激酶 B1（LKB1）通过调节能量传感器 AMP 激活的蛋白激酶（AMPK）的活性，在调节能量稳态方面发挥着重要作用。然而，LKB1 功能的调控仍知之甚少。在这里，我们证明孤儿核受体 Nur77 与 LKB1 结合并将其隔离在核内，从而减弱 AMPK 的激活。这种 Nur77 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，TMPA 与 Nur77 具有高亲和力和特定结合位点相互作用。Nur77 与 TMPA 的结合导致 LKB1 释放并易位到细胞质中，以磷酸化 AMPKα。此外，TMPA 可有效降低 II 型 db/db 糖尿病小鼠和高脂肪饮食及链脲佐菌素诱导的糖尿病小鼠的血糖，并缓解胰岛素抵抗，但对 Nur77 基因敲除的糖尿病同窝仔鼠则无效。本研究深入了解了 LKB1-AMPK 轴的调控机制，并提示 Nur77 是设计和开发治疗代谢性疾病的治疗方法的新的、可行的靶标。
