Open AccessGlucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl‐CoA carboxylase by cyclic‐AMP‐dependent protein kinase
Author(s) -
HOLLAND Ross,
WITTERS Lee A.,
HARDIE D. Grahame
Publication year - 1984
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1984.tb08105.x
Subject(s) - pyruvate carboxylase , biochemistry , glucagon , phosphorylation , protein kinase a , acetyl coa carboxylase , fatty acid synthesis , enzyme , activator (genetics) , kinase , atp citrate lyase , protein phosphorylation , chemistry , adenylate kinase , biology , citrate synthase , hormone , gene
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 K a for citrate; and (4) all of these effects occur at physiological concentrations of glucagon identical to those producing inhibition of fatty acid synthesis.