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Abstract

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.

  • Compound C21H32O6

    Ethyl 2-(2,3,4-trimethoxy-6-octanoylphenyl)acetate

  • Compound C19H28O3

    3-Heptyl-5,6,7-trimethoxy-1H-indene

  • Compound C19H30O5

    1-Heptyl-4,5,6-trimethoxy-2,3-dihydro-1H-indene-1,2-diol

  • Compound C19H28O5

    2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetaldehyde

  • Compound C19H28O6

    2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetic acid

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Change history

  • 28 September 2012

    In the version of this article initially published online, the name of the contributing author Chawnshang Chang was misspelled. The error has been corrected for the PDF and HTML versions of this article.

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Acknowledgements

We are grateful to P. Li (Tsinghua University) for the plasmids encoding AMPKβ, AMPKγ and AMPKα(1–312) and to J. Wu (Tsinghua University) for the tricistronic expression plasmids for all three subunits of AMPK. This work was supported by the grants from '973' Project of the Ministry of Science and Technology (2011CB910802), the National Natural Science Fund of China (30810103905, 30630070, 30921005 and 30870479), the Program of Introducing Talents of Discipline to Universities (B12001 and B06016) and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2012KF002). We also gratefully acknowledge the use of Beamline BL17U1 at Shanghai Synchrotron Radiation Facility for crystallographic data collection.

Author information

Author notes

    • Yan-yan Zhan
    • , Yan Chen
    •  & Qian Zhang

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.

    • Yan-yan Zhan
    • , Yan Chen
    • , Qian Zhang
    • , Min Tian
    • , Hang-zi Chen
    • , Lian-ru Zhang
    • , Jian-ping He
    • , Wei-jia Wang
    • , Rong Wu
    • , Yuan Wang
    • , Chunfang Shi
    • , Kai Yang
    • , An-zhong Li
    • , Yong-zhen Xin
    • , Terytty Yang Li
    • , James Y Yang
    • , Zhong-hui Zheng
    • , Chun-dong Yu
    • , Sheng-Cai Lin
    • , Tianwei Lin
    •  & Qiao Wu
  2. Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, China.

    • Jia-jia Zhuang
    • , Hong-kui Zhang
    •  & Pei-qiang Huang
  3. George H. Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.

    • Chawnshang Chang

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Contributions

Q.W. and T.L designed the experiments and wrote the manuscript. Y.Z., Y.C., M.T., H.C., J.H., W.W., R.W., Y.W., A.L., Y.X. and T.Y.L. carried out the experiments on molecular and cellular biology as well as studies on mouse models. Q.Z., L.Z., C.S. and K.Y. carried out the structural studies. J.Z. and H.Z. synthesized the chemical compounds, and S.-C.L., P.H., C.C., J.Y.Y., Z.Z. and C.Y. were involved in the design of this project as well as in reading and commenting on the manuscript, and S.-C.L. helped on writing the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tianwei Lin or Qiao Wu.

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https://doi.org/10.1038/nchembio.1069

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