Hyperthyroidism impairs the activation of glycogen phosphorylase by epinephrine in rat hepatocytes.

The activation of glycogen phosphorylase by epinephrine was examined in hepatocytes from fed female rats administered 0.25 mg of triiodothyronine per kg of body weight daily for 2 days. Basal cyclic AMP accumulation by the hepatocytes was not altered by the thyroid hormone administration. Basal glycogen phosphorylase a activities were 1.18 f 0.07 units/mg of protein in control and 0.37 -+ 0.04 unit/mg of protein in triiodothyronine-treated rat hepatocytes, representing a 70% reduction in the basal activity of this enzyme. Phosphorylase a activity of hepatocytes in response to 10 epinephrine increased 1.2 units/mg of protein (100% over basal) in those from control rats, while increasing only 0.2 unit/mg of protein (50% over basal) in hepatocytes from the triiodothyronine-treated rats. Total glycogen phosphorylase activity was reduced 25% with respect to control levels in hepatocytes from rats treated with thyroid hormones, a change of insufficient magnitude to account for the dramatic reduction in the basal phosphorylase a activity. To explore further the basis for the reduced basal phosphorylase activity, both the phosphorylase 6 kinase and phosphorylase phosphatase activities were measured. Thyroid hormone treatment reduced hepatocyte phosphorylase b kinase activity 178, while increasing phosphorylase phosphatase activity by 50%. Although triiodothyronine treatment did not influence the affinity of aadrenergic receptors of hepatocyte membrane fractions, it did result in a 70% reduction in the number of al-adrenergic receptor sites per mg of membrane protein. These data suggest that thyroid hormones exert their influence on the hormonal regulation of hepatic glycogenolysis via (i) altering protein phosphatase activity which regulates phosphorylase and phosphorylase kinase and (ii) modulating the number of al-adrenergic receptor sites which apparently transduce epinephrine binding into a-adrenergic control of hepatic glycogenolysis.