title: Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase.
abstract: If isolated rat hepatocytes are preincubated for 90 min before addition of hormone, glucagon causes a significant (50%) decrease in fatty acid synthesis without concomitant large decreases in the cellular content of the allosteric activator, citrate. We present evidence that this inhibition can be entirely accounted for by the phosphorylation of the rate-limiting enzyme, acetyl-CoA carboxylase, by cyclic-AMP-dependent protein kinase. In particular: (1) the effect is associated with a 50% decrease in acetyl-CoA carboxylase activity (measured at physiological citrate concentration) which survives purification of the enzyme; (2) the effect is associated with a selective increase in the phosphorylation of a chymotryptic peptide (peptide 1) which is identical to the peptide containing the major site phosphorylated on purified acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase; (3) the effects of glucagon on the kinetic parameters of the enzyme are very similar to the effect of phosphorylation of the purified enzyme, i.e. a decrease in V and an increase in Ka for citrate; and (4) all of these effects occur at physiological concentrations of glucagon identical to those producing inhibition of fatty acid synthesis.
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D002951:Citrates / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D005934:Glucagon / Q000494:pharmacology*; D066298:In Vitro Techniques; D008025:Ligases / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002951:Citrates; D005227:Fatty Acids; D005934:Glucagon; D011494:Protein Kinases; D008025:Ligases; D000103:Acetyl-CoA Carboxylase