title: 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor α-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein kinase-independent.
abstract: 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR), a prodrug activator of AMP-activated protein kinase (AMPK), increased hepatic expression of cytochrome P450 4a10, 4a14, and 4a31 mRNAs 2-, 3-, and 4-fold, respectively, and liver microsomal lauric acid ω-hydroxylation increased 2.8-fold. Likewise, mRNA levels of the peroxisome proliferator-activated receptor α (PPARα)-responsive genes, Acox1, Acadm, Cpt1a, and Fabp1, were also increased by AICAR treatment. AICAR did not elicit these changes in PPARα null mice. In isolated murine hepatocytes, AICAR and adenosine produced similar effects, and these responses were blocked by the PPARα antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). Inhibition of AMPK using compound C (dorsomorphin or 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine) did not block the induction of the PPARα-responsive genes by AICAR or adenosine, and 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (A-769662), a non-nucleoside, direct activator of AMPK, did not increase expression of PPARα-responsive genes. An inhibitor of adenosine kinase, 5-iodotubercidin, blocked these responses, suggesting that the phosphorylation of AICAR and adenosine to AICAR 5'-monophosphate (ZMP) or AMP, respectively, was required. Concentrations of ZMP and AMP were elevated and ATP levels diminished at 24 h. The PPARα-dependent responses were associated with increased concentrations of oleic acid, a potent PPARα agonist, and diminished levels of oleoyl-CoA. Oleoyl-CoA synthase activity was inhibited by ZMP and AMP with IC(50) values of 0.28 and 0.41 mM, respectively. These results suggest that PPARα is activated by increased concentrations of free fatty acids that may arise from impaired fatty acid metabolism caused by altered levels of ATP, AMP, and ZMP after AICAR or adenosine treatment.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM-255, La Jolla, CA 92037, USA.
authors: Namandjé N
authors: NN
authors: Bumpus
authors: Eric F
authors: EF
authors: Johnson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003066:Coenzyme A Ligases / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005822:Genetic Vectors; D022781:Hepatocytes; D006900:Hydroxylation / Q000187:drug effects; D007850:Lauric Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D047493:PPAR alpha / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: C512110:Cyp4a10 protein, mouse; C436963:Cyp4a14 protein, mouse; D005230:Fatty Acids, Nonesterified; D007850:Lauric Acids; D047493:PPAR alpha; D012265:Ribonucleotides; C030358:lauric acid; D000620:Aminoimidazole Carboxamide; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D055372:AMP-Activated Protein Kinases; D003066:Coenzyme A Ligases; C031143:AICA ribonucleotide; D000241:Adenosine