Effects of 5-iodotubercidin on hepatic fatty acid metabolism mediated by the inhibition of acetyl-CoA carboxylase.
Diverse mechanisms of action have been proposed for 5-iodotubercidin, although it is widely used as an adenosine kinase inhibitor that consequently interferes with the metabolism of adenosine and adenine nucleotides. Incubation of rat hepatocytes with iodotubercidin produced important effects on lipid metabolism. (i) Both acetyl-CoA carboxylase and fatty acid synthesis de novo were inhibited in parallel by iodotubercidin, with no change in the activity of fatty acid synthase. The inhibition of both activities showed a comparable dependence on iodotubercidin concentration and was accompanied by a similar decrease (about 60%) in the intracellular malonyl-CoA concentration. (ii) Iodotubercidin stimulated palmitate oxidation, although octanoate oxidation was unaffected. However, this effect can be attributed to the decrease of malonyl-CoA concentration and the concomitant relief of the inhibition of carnitine palmitoyltransferase I, because the activity of this enzyme was found unaltered when determined in cells permeabilized with digitonin. (iii) Iodotubercidin also inhibited cholesterol synthesis de novo. Results, thus, indicate that iodotubercidin increases fatty acid oxidation activity of the liver at the expense of lipogenesis, and we suggest that these effects on fatty acid metabolism are mediated by the inhibition of acetyl-CoA carboxylase, probably due to a more than twice increase in the AMP/ATP ratio and the concomitant stimulation of the AMP-activated protein kinase.
García-Villafranca
Javier
J
Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, E-28040, Madrid, Spain.
Castro
José
J
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005227:Fatty Acids; C034214:5-iodotubercidin; D002334:Carnitine O-Palmitoyltransferase; D000103:Acetyl-CoA Carboxylase; D014372:Tubercidin