Acetyl-CoA carboxylase, ATP-citrate lyase

Glucagon inhibits fatty acid synthesis in liver [123] and the inhibition is correlated with decreased activity of acetyl-CoA carboxylase [124,125], The inhibition of the enzyme is due to its phosphorylation by cAMP-dependent protein kinase [125,126] which causes a decrease in the Vm.M and an increase in the Ku for citrate [126], 

Incubation of hepatocytes with glucagon also increases the phosphorylation of another lipogenic enzyme ATP-citrate lyase [127,128], The purified enzyme is also phosphorylated by cAMP-dependent protein kinase in vitro [128,129] resulting in a 2-fold increase in the Km for ATP [130], However, it is unclear what role this plays in the inhibition of lipogenesis. 

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

Glucagon increases cytosolic Ca2+ both by mobilizing intracellular Ca2+ stores and promoting Ca2+ influx across the plasma membrane. The internal Ca2+ stores mobilized by glucagon appear to be the same as those acted on by other Ca2+-mo-bilizing hormones [5,9,143] (Fig 9), and there is evidence that the plasma membrane Ca2+ channel(s) controlled by glucagon are the same as those controlled by vasopressin or phenylephrine [144,145], 

In addition to mobilizing internal Ca2+, glucagon promotes the net entry of extracellular Ca2+ into hepatocytes [144,145]. The effect is apparently due to increased influx of Ca2+ through a plasma membrane channel(s) [144,145], but there is also inhibition of the plasma membrane Ca2+ ATPase-pump [150-153], The mechanism by which glucagon stimulates Ca2+ entry is unknown, but it almost certainly involves cAMP since the effect can be mimicked by forskolin, dibutyryl cAMP and /3-adrenergic agonists [144,145]. It may involve cAMP-dependent phosphorylation of a Ca2+ channel analogous to the situation in cardiac and skeletal muscle [154-156], but this is strictly speculative. 

---