Mechanisms of hormonal regulation of liver metabolism.
The mechanism of actions of glucagon, alpha- and beta-adrenergic agonists, vasopressin and angiotensin II in the liver proposed in this article are summarized in Fig. 8. The actions of glucagon and beta-adrenergic agonists in liver can be entirely ascribed to their interaction with specific plasma membrane receptors which activate adenylate cyclase leading to the intracellular accumulation of cAMP and activation of cAMP-dependent protein kinase. This enzyme phosphorylates phosphorylase b kinase, glycogen synthase, L-type pyruvate kinase, and other liver proteins resulting in alterations in their activities which can account for several of the known hepatic responses to glucagon. There is no clear evidence that Ca2+ ions are involved in the hepatic actions of this hormone. Glucocorticoids, but not thyroid hormones, are required for normal responsiveness of the liver to glucagon. The steroids do not modify cAMP accumulation or cAMP-dependent protein kinase activation, but may act by modulating the action of the kinase on its substrates. Glucocorticoids and thyroid hormones decrease beta-adrenergic responses in the liver apparently by decreasing the number of beta-receptors. Insulin inhibits the actions of physiological concentrations of glucagon by decreasing cAMP accumulation: its mechanism of action is unknown. The actions of alpha-adrenergic agonists, vasopressin and angiotensin II on the liver resemble those of glucagon, but do not involve accumulation of cAMP or activation of cAMP-dependent protein kinase. These agents appear to act by increasing cytosolic Ca2+ thus altering the activities of Ca2+-sensitive enzymes such as phosphorylase b kinase and calmodulin-dependent glycogen synthase kinase. Their receptors appear to be located exclusively on the plasma membrane and a major mechanism by which they raise cytosolic Ca2+ is by inducing the release of this cation from mitochondria. These considerations imply the existence of an intracellular messenger(s) for these agents which is generated at the plasma membrane in response to receptor activation and exerts effects on mitochondria or perhaps other intracellular structures. Glucocorticoids and thyroid hormones increase alpha-adrenergic responses in the liver apparently by increasing the number of alpha-receptors. Insulin inhibits the responses of the liver to alpha-agonists, but not to vasopressin or angiotensin II.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D004789:Enzyme Activation; D005934:Glucagon / Q000494:pharmacology; D006006:Glycogen Synthase / Q000378:metabolism; D006728:Hormones / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D006005:Phosphorylases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D014667:Vasopressins / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D006728:Hormones; D007328:Insulin; D014667:Vasopressins; D000804:Angiotensin II; D010656:Phenylephrine; D005934:Glucagon; D000242:Cyclic AMP; D006005:Phosphorylases; D006006:Glycogen Synthase; D011494:Protein Kinases