Effects of extracellular ATP on hepatic fatty acid metabolism.
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 Ca2+ -depleted hepatocytes. Incubation of hepatocytes with thapsigargin, 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ), or A-23187, compounds that increase cytosolic free Ca2+ concentration ([Ca2+]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 nonaddictive manner with respect to extracellular ATP. The inhibitory effect of extracellular ATP on ACC activity was also evident in the presence of bisindolyl-maleimide, 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 [Ca2+]i, whereas CPT-I may be inhibited by extracellular ATP through a PKC-dependent mechanism.
Guzmán
M
M
Department of Biochemistry and Molecular Biology I, Faculty of Biology, Complutense University, Madrid, Spain. mgp@solea.quim.ucm.es
Velasco
G
G
Castro
J
J
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D005227:Fatty Acids; D008055:Lipids; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D000103:Acetyl-CoA Carboxylase; D002118:Calcium