科学家在本周的《自然—化学生物学》撰文称他们发现了腺苷酸活化蛋白激酶(AMPK)的激活机理,AMPK是一种“代谢感应器”,对保持细胞的能量平衡具有重要作用,其已被证明可作为糖尿病治疗的有效靶点。
该项研究有助我们深入了解AMPK激活的基本调控,并为糖尿病治疗研究提供了一种新的治疗途径。
Qiao Wu, Tianwei Lin等人发现一种包含Nur77的信号通路,Nur77是一种孤核受体,通过阻断AMPK的激活物质LKB1实现对AMPK的负调控。
研究人员最近发现一种化合物可以阻碍Nur77对LKB1的作用从而使LKB1能顺利激活AMPK,通过研究该化合物的作用机理,研究人员最终确定了上述信号通路。在多个糖尿病患病小鼠模型中,该化合物能够改善血糖水平、胰岛素水平以及葡萄糖负荷反应。
该化合物能否应用到临床使用中还需更进一步的试验确认,但是这种通路的发现为科学家通过激活AMPK来治疗糖尿病提供了新机遇。(生物谷Bioon.com)
doi:10.1038/nchembio.1069
PMC:
PMID:
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.