Hormonal regulation of liver hexokinase activity

Abstract

Summary 1. In liver cells of the rabbit embryo hexokinase activity is much higher, its intracellular distribution being different from that found in mature animals (higher activity of hexokinase bound to mitochondria, occurrence of hexokinase in microsomes). Hexokinase activity of cell fractions decreases with embryonic age. Glucose-6-phosphate dehydrogenase activity of embryonic liver is also shown to be much higher than in adult rabbits and to decrease gradually towards term. Glucose-6-phosphatase activity is absent at early embryonic periods and shortly before birth, rising up to levels found in adult rabbits shortly after birth. 2. Absence of any “barrier” for penetration of glucose in liver cells provides favorable conditions for studying hormonal influences (glucocorticosteroids and insulin) on the activity of HK and other enzymes of liver glucose-6-phosphate metabolism. 3. Glucocorticoid (cortisone acetate) administration to adult rabbits and rats provokes inhibition of hexokinase and glucose-6-phosphate dehydrogenase dissolved in hyaloplasm of liver cells, inhibition of HK bound to mitochondria being more slow to set in. 4. 6. After cortisone acetate administration, hepatic glucose-6-phosphatase activity is shown to rise considerably, both in the adult animal and embryo. 7. Dissimilar reactivity to the effects of glucocorticoids displayed by hexokinase or glucose-6-phosphate dehydrogenase on one hand, and by glucose-6-phosphatase on the other, in cell fractions from embryonic liver, apparently depends on different mechanisms underlying the effects exerted by these hormones on activity or synthesis of the enzymes under consideration. 8. Hexokinase activity diminishes considerably in liver cell fractions from alloxan diabetic rabbits. Insulin administration restores mitochondrial hexokinase activity rapidly, while hexokinase dissolved in hyaloplasm is restored much more slowly. 9. The effect of insulin in vitro has been studied under conditions ensuring against its destruction by insulinase. Rapid reversal by insulin of the inhibiting influence of glucocorticoids on hepatic hexokinase and glucose-6-phosphate dehydrogenase activities of alloxan diabetic or of cortisonetreated animals, as well as reversal of their glucose-6-phosphatase enhancing influence, enzymatic activity tending to approach normal values have been demonstrated to occur in vitro . These facts provide evidence for a direct action of insulin on hepatic glucose-6-phosphate metabolism. 10. The inhibiting effect of cortisone (dissolved in β -lipoprotein) and of β -lipoprotein from blood plasma of alloxan diabetic or fasted animals on yeast hexokinase activity, as well as reversal of the inhibition by insulin, have been confirmed. Inhibition of yeast hexokinase by cortisone is shown to occur even after N-ethylmaleimide assay, binding SH groups of the enzyme. Cortisone inhibits phosphorylation of glucose and mannose by yeast hexokinase, but fails to influence phosphorylation of 2-desoxyglucose or fructose. Insulin produces rapid reversal of the inhibiting effect of cortisone on yeast hexokinase, activity of the enzyme being restored entirely. The influence of insulin fails to take place after the SH groups of hexokinase have been bound (by N-ethylmaleimide). Insulin may, therefore, be assumed to bind these groups of yeast hexokinase. 11. The block of hepatic glucokinase reaction occurring in diabetes results in a lowered level of energy metabolism and reduced energy supply to synthesis in the liver. 12. Primary disturbance of hepatic glucose-6-phosphate metabolism proves to be a significant factor in the onset of secondary metabolic disorders, affecting the organ and the body as a whole.