There is increasing evidence for the existence of intrahepatic regulat
ion of glucose metabolism by Kupffer cell products. Nitric oxide (NO)
is known to inhibit gluconeogenic flux through pyruvate carboxylase an
d phosphoenolpyruvate carboxykinase. However, NO may also influence gl
ucose metabolism at other levels. Using hepatocytes from fasted rats i
ncubated with the NO-donor S-nitroso-N-acetylpenicillamine, we have no
w found that the synthesis of glycogen from glucose is even more sensi
tive to inhibition by NO than gluconeogenesis. Inhibition of glycogen
production by NO was accompanied by a rise in intracellular glucose 6-
phosphate and UDPglucose. Activity of glycogen synthase, as measured i
n extracts of hepatocytes after the cells had been exposed to NO, was
decreased. Experiments with gel-filtered liver extracts revealed that
inhibition of glycogen synthase was caused by an inhibitory effect of
NO on the conversion of glycogen synthase 6 into glycogen synthase a.