Effects of extracellular ATP on hepatic fatty acid metabolism
Guzmán, M.; Velasco, G.; Castro, J.
American Journal of Physiology 270(4 Pt 1): G701-G707
1996
ISSN/ISBN: 0002-9513 PMID: 8928801 Document Number: 466312
Incubation of rat hepatocytes with extracellular ATP inhibited acetyl-CoA carboxylase (ACC) activity and fatty acid synthesis de novo, with a concomitant decrease of intracellular malonyl-CoA concentration. However, both carnitine O-palmitoyltransferase I (CPT-I) activity and ketogenesis from palmitate were inhibited in parallel by extracellular ATP. The inhibitory effect of extracellular ATP on ACC and CPT-I activities was not evident in Ca-2+-depleted hepatocytes. Incubation of hepatocytes with thapsigargin, 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ), or A-23187, compounds that increase cytosolic free Ca-2+ concentration ((Ca-2+)-i), depressed ACC activity, whereas CPT-I activity was unaffected. The phorbol ester 4-beta-phorbol 12-beta-myristate 13-alpha-acetate (PMA) increased ACC activity, whereas it decreased CPT-I activity in a nonadditive manner with respect to extracellular ATP. The inhibitory effect of extracellular ATP on ACC activity was also evident in the presence of bisindolylmaleimide, a specific inhibitor of protein kinase C (PKC), whereas this compound abolished the extracellular ATP-mediated inhibition of CPT-I. In addition, the PMA-induced inhibition of CPT-I was not potentiated by thapsigargin, BHQ, or A-23187. Results thus show 1) that the intracellular concentration of malonyl-CoA is not the factor responsible for the inhibition of hepatic long-chain fatty acid oxidation by extracellular ATP, and 2) that the inhibition of ACC by extracellular ATP may be mediated by an elevation of (Ca-2+)-i, whereas CPT-I may be inhibited by extracellular ATP through a PKC-dependent mechanism.