The 5'-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex.
5-Amino-4-imidazolecarboxamide riboside (AICAR) is known to stimulate rat liver 5'-AMP-activated protein kinase (AMPK). AMPK is the mammalian homologue of Snf1p in yeast, involved in derepression of glucose-repressed genes. We used AICAR to test if AMPK could also play a role in the regulation of glucose-dependent genes in mammalian cells. At a concentration which induces phosphorylation-dependent inactivation of HMG-CoA reductase, AICAR blocked glucose activation of three glucose responsive genes, namely L-type pyruvate kinase (L-PK), Spot 14 and fatty acid synthase genes in primary cultured hepatocytes, but was without any action on glucose phosphorylation to glucose 6-phosphate and on expression of PEPCK, albumin and beta-actin genes. AICAR was also found to inhibit activation of the L-PK gene promoter by glucose in transiently transfected hepatoma cells. Therefore our results suggest that AMPK is probably involved in the glucose signal pathway regulating gene expression in the liver.
Institut Cochin de Génétique Moléculaire, INSERM, Unité 129, Paris, France.
I
I
Leclerc
A
A
Kahn
B
B
Doiron
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular; D002478:Cells, Cultured; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D012265:Ribonucleotides; C051065:THRSP protein, human; C501477:Thrsp protein, mouse; C501478:Thrsp protein, rat; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D019298:Glucose-6-Phosphate; D064429:Fatty Acid Synthases; D011494:Protein Kinases; C071570:SNF1-related protein kinases; D011770:Pyruvate Kinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose