title: The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Zhan
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jia-jia
authors.initials: JJ
authors.lastname: Zhuang
authors.forename: Min
authors.initials: M
authors.lastname: Tian
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Lian-ru
authors.initials: LR
authors.lastname: Zhang
authors.forename: Hong-kui
authors.initials: HK
authors.lastname: Zhang
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: He
authors.forename: Wei-jia
authors.initials: WJ
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunfang
authors.initials: C
authors.lastname: Shi
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: An-zhong
authors.initials: AZ
authors.lastname: Li
authors.forename: Yong-zhen
authors.initials: YZ
authors.lastname: Xin
authors.forename: Terytty Yang
authors.initials: TY
authors.lastname: Li
authors.forename: James Y
authors.initials: JY
authors.lastname: Yang
authors.forename: Zhong-hui
authors.initials: ZH
authors.lastname: Zheng
authors.forename: Chun-dong
authors.initials: CD
authors.lastname: Yu
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Pei-qiang
authors.initials: PQ
authors.lastname: Huang
authors.forename: Tianwei
authors.initials: T
authors.lastname: Lin
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008958:Models, Molecular; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D013311:Streptozocin; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; C578196:ethyl 2-(2,3,4-trimethoxy-6-(1-octanoyl)phenyl)acetate; D013311:Streptozocin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases