The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
Autor: | Qiao Wu, Zhonghui Zheng, Jia-Jia Zhuang, Terytty Yang Li, Chunfang Shi, Wei-jia Wang, Yan Chen, Yong-zhen Xin, Hang-zi Chen, Pei-Qiang Huang, Yuan Wang, Jian-ping He, An-zhong Li, Lianru Zhang, Yan-yan Zhan, Rong Wu, Hong-Kui Zhang, James Y. Yang, Chun-dong Yu, Sheng-Cai Lin, Kai Yang, Chawnshang Chang, Qian Zhang, Tianwei Lin, Min Tian |
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Rok vydání: | 2012 |
Předmět: |
Blood Glucose
Male Models Molecular Nerve growth factor IB Mice Obese Biology AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Streptozocin Diabetes Mellitus Experimental Enzyme activator Mice Structure-Activity Relationship AMP-activated protein kinase AMP-Activated Protein Kinase Kinases Nuclear Receptor Subfamily 4 Group A Member 1 Animals Humans Phosphorylation Protein kinase A Molecular Biology Cells Cultured Phenylacetates Mice Knockout Kinase AMPK Cell Biology Enzyme Activation Mice Inbred C57BL Protein Transport HEK293 Cells Biochemistry Nuclear receptor biology.protein Insulin Resistance |
Zdroj: | Nature chemical biology. 8(11) |
ISSN: | 1552-4469 |
Popis: | 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. |
Databáze: | OpenAIRE |
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