Decrease and Inhibition of Liver Glycogen Phosphorylase After Fructose: An Experimental Model for the Study of Hereditary Fructose Intolerance

Abstract

Inhibition of liver phosphorylase may play an important role in the fructose-induced hypoglycemia of hereditary fructose intolerance. This report is an in vivo study of the effects of fructose on selected metabolic intermediates and on phosphorylase activity in the liyers of young mice. Phosphorylase activity in liver homogenate was measured in the direction of glycogen breakdown. The Km for Pi was 1.12 mM and the Ki for fructose-1-phosphate was 1.19 mM. This finding is particularly relevant since twenty minutes after fructose injection (30 mmoles per kilogram intraperitoneally) liver Pi was reduced 50 per cent, p < 0.001 and fructose-1-phosphate was increased fifty fold, p < 0.001. Liver glucose was unchanged. In controls, activity of phosphorylase was dependent on the state of the animals: 2.43 ± 0.31 μ/moles/gm. min−1 in anesthetized mice, 9.55 ± 0.55 in excited animals. Under these same conditions phosphorylase activity in fructose-injected littermates was reduced 40 to 80 per cent (mean 48 per cent, p = 0.002). At the concentrations of Pi and fructose-1-phosphate found in liver after fructose, phosphorylase activity in vitro was inhibited 88 per cent (p < 0.001). In vivo the activity of liver phosphorylase is apparently reduced by two mechanisms, a conversion to the inactive form and an inhibition of the remaining active enzyme by reduced Pi and elevated fructose-1-phosphate levels. We have postulated that de novo synthesis of glucose from fructose in normal animals could mask any hypoglycemia which might result from reduced liver phosphorylase activity. The in vivo effect of glucose injection on liver phosphorylase was also studied. At high levels of enzyme activity, glucose reduced phosphorylase activity by 43 per cent, p = 0.012; at low levels of enzyme activity, glucose had no effect.