The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK

Nat Chem Biol. 2012 Nov;8(11):897-904. doi: 10.1038/nchembio.1069. Epub 2012 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Blood Glucose / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Enzyme Activation / drug effects
  • HEK293 Cells
  • Humans
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Models, Molecular
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phenylacetates / chemistry
  • Phenylacetates / pharmacology*
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Streptozocin
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • ethyl 2-(2,3,4-trimethoxy-6-(1-octanoyl)phenyl)acetate
  • Streptozocin
  • STK11 protein, human
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases

Associated data

  • PDB/3V3E
  • PDB/3V3Q
  • PubChem-Substance/143504697
  • PubChem-Substance/143504698
  • PubChem-Substance/143504699
  • PubChem-Substance/143504700
  • PubChem-Substance/143504701