科學(xué)家在本周的《自然—化學(xué)生物學(xué)》撰文稱他們發(fā)現(xiàn)了腺苷酸活化蛋白激酶（AMPK）的激活機(jī)理,，AMPK是一種“代謝感應(yīng)器”，對(duì)保持細(xì)胞的能量平衡具有重要作用,，其已被證明可作為糖尿病治療的有效靶點(diǎn)。
該項(xiàng)研究有助我們深入了解AMPK激活的基本調(diào)控，并為糖尿病治療研究提供了一種新的治療途徑,。
Qiao Wu, Tianwei Lin等人發(fā)現(xiàn)一種包含Nur77的信號(hào)通路，Nur77是一種孤核受體,，通過阻斷AMPK的激活物質(zhì)LKB1實(shí)現(xiàn)對(duì)AMPK的負(fù)調(diào)控,。
研究人員最近發(fā)現(xiàn)一種化合物可以阻礙Nur77對(duì)LKB1的作用從而使LKB1能順利激活A(yù)MPK，通過研究該化合物的作用機(jī)理,，研究人員最終確定了上述信號(hào)通路,。在多個(gè)糖尿病患病小鼠模型中,，該化合物能夠改善血糖水平、胰島素水平以及葡萄糖負(fù)荷反應(yīng),。
該化合物能否應(yīng)用到臨床使用中還需更進(jìn)一步的試驗(yàn)確認(rèn),，但是這種通路的發(fā)現(xiàn)為科學(xué)家通過激活A(yù)MPK來治療糖尿病提供了新機(jī)遇。（生物谷Bioon.com）
doi:10.1038/nchembio.1069
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The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
Yan-yan Zhan, Yan Chen, Qian Zhang, Jia-jia Zhuang, Min Tian, Hang-zi Chen, Lian-ru Zhang, Hong-kui Zhang, Jian-ping He, Wei-jia Wang, Rong Wu, Yuan Wang, Chunfang Shi, Kai Yang, An-zhong Li, Yong-zhen Xin, Terytty Yang Li,1 James Y Yang, Zhong-hui Zheng, Chun-dong Yu, Sheng-Cai Lin, Chawn-shang Chang, Pei-qiang Huang, Tianwei Lin & Qiao Wu
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.
