KINETIC-ANALYSIS OF GLYCOGEN-SYNTHASE AND PDC IN CIRRHOTIC RAT-LIVER AND SKELETAL-MUSCLE

Glycogen synthase (GS) and pyruvate dehydrogenase complex (PDC) were k inetically analyzed in the liver and skeletal muscle of fasted and ref ed rats with thioacetamide-induced cirrhosis of the liver. In control rats, refeeding induced a 54% decrease in the A(0.5) for glucose B-pho sphate (G-6-P) of hepatic GS (P < 0.001), reflecting allosteric activa tion of the enzyme. In skeletal muscle the A(0.5) for G-6-P did not ch ange after refeeding, whereas the activity ratio increased by 56% (P < 0.01), indicating a greater percentage of the active G-6-P-independen t form of the enzyme. In cirrhotic rats, neither the A(0.5) for G-B-P of liver GS nor the activity ratio of muscle GS was influenced by refe eding. Consequently, glycogen replenishment was significantly impaired both in the liver (2.56 +/- 0.2 vs. 5.11 +/- 0.4 g/100 g; P < 0.001) and skeletal muscle (0.45 +/- 0.01 vs. 0.52 +/- 0.02 g/100 g; P < 0.01 ). Refeeding increased the percentage of the active form of hepatic PD C both in control (+88%; P < 0.01) and cirrhotic rats (+91%; P < 0.001 ). In the latter, however, the rates of total and active PDC were sign ificantly lower than in controls [-44% and -40% in fasted (P < 0.005) and refed (P < 0.005) rats, respectively]. Muscle PDC kinetics (both m aximal velocity and Michaelis constant) and the percent active form we re identical in cirrhotic and control rats, regardless of the nutritio nal state. The data indicate that, in rats with experimental cirrhosis , liver and muscle GS are insensitive to allosteric activation by G-6- P and covalent modification by insulin, respectively. This is likely t o account for the reduced glycogen content in both tissues. Hepatic, b ut not muscle, PDC is less active in cirrhotic animals.