title: The adenosine derivative 2',3',5'-tri-O-acetyl-N6-(3-hydroxylaniline) adenosine activates AMPK and regulates lipid metabolism in vitro and in vivo.
abstract: OBJECTIVE
  Our overall objective was to investigate the effect of the adenosine derivative 2',3',5'-tri-O-acetyl-N6-(3-hydroxylaniline) adenosine (WS010117) on AMP-activated protein kinase (AMPK) activation and lipid metabolism and to also assess the underlying mechanisms involved in these processes.
  
  
  METHODS
  HepG2 cells and hamsters fed a high-fat diet were used to test the effects of WS010117 on lipid metabolism. Western blots, chemical intervention, HPLC, SAMS peptide assay, (14)C-labelled acetate and palmitate assays, molecular docking assay and siRNA targeting the AMPK γ1 subunit were used to investigate the effect of WS010117 on AMPK activation as well as the underlying mechanism involved in this activation.
  
  
  RESULTS
  WS010117 treatment resulted in the dose-dependent activation of AMPK in HepG2 cells, increasing lipid oxidation and decreasing lipid biosynthesis. In hamsters that were fed a high-fat diet, WS010117 treatment (1.5-6 mg/kg) significantly inhibited the increase in lipid accumulation. WS010117-induced AMPK activation was essentially abolished by treatment with compound C, and the addition of WS010117 did not alter the intracellular AMP:ATP ratio. In HeLa cells endogenously lacking LKB1, WS010117-mediated AMPK activation was not impaired, even following co-treatment with STO-609, a selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). The results from the molecular docking assays and experiments targeting the AMPK γ1 subunit with siRNA indicated that WS010117 may activate AMPK by binding to and regulating the γ subunit of AMPK.
  
  
  CONCLUSIONS
  Our data indicate that WS010117 can regulate lipid metabolism through the activation of AMPK. WS010117 may activate AMPK by binding to and regulating the AMPK γ subunit.
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Ze-qin
authors.initials: ZQ
authors.lastname: Lian
authors.forename: Ling-hui
authors.initials: LH
authors.lastname: Sheng
authors.forename: Chong-ming
authors.initials: CM
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan-shen
authors.initials: YS
authors.lastname: Guo
authors.forename: Hai-bo
authors.initials: HB
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008647:Mesocricetus; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D004041:Dietary Fats; C561084:O2',O3',O5'-triacetyl-N6-(3-hydroxylaniline)adenosine; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases; D000241:Adenosine