show a reduction in nonoxidative glucose metabolism, 3,4 find-Liver and skeletal muscle glycogen metabolism were ings compatible with impaired glycogen synthesis. 5 In supinvestigated in rats 1 and 4 weeks after bile duct ligation port of this concept, glycogen synthase activity has been (BDL) and in pair-fed, sham-operated control rats. Livfound to be reduced in skeletal muscle from cirrhotic paers were subjected to morphometric analysis to express tients. 5 Similarly, in rats with carbon tetrachloride (CCl 4 )glycogen content and enzyme activities per mL hepatoinduced cirrhosis, incorporation of [ 14 C]-glucose into glycogen cytes. One week after BDL, the hepatic glycogen content in skeletal muscle and diaphragm was reduced, suggesting was 28.8 { 13.8 versus 38.6 { 16.4 mg/mL hepatocyte in impaired glycogen synthesis. 6 In addition, in rats with CCl 4 -BDL and control rats, respectively. Total activity of glyinduced cirrhosis, the hepatic glycogen content has been decogen synthase (50.2 { 7.0 vs. 63.5 { 9.4 mU/mL hepatoscribed to be reduced per gram liver and per hepatocyte cytes) and glycogen phosphorylase (59.4 { 12.9 vs. 90.8 { 18.9 U/mL) were significantly reduced in BDL whereas whereas skeletal muscle glycogen content was unchanged as the active fraction of glycogen synthase (27 { 6 vs. 38 { compared with pair-fed control rats. 7 During starvation, rats 5%) but not of glycogen phosphorylase was reduced. The with CCl 4 -induced cirrhosis lost their hepatic glycogen stores skeletal muscle glycogen content was not different bemore rapidly than control rats, 7,8 a finding which was accomtween BDL and control rats. Four weeks after BDL, hepanied by a faster increase in acylcarnitines and nonesteripatic glycogen content was further reduced (20.5 { 14.2 fied fatty acids in plasma, suggesting an accelerated transivs. 52.9 { 6.4 mg/mL). Total activity of glycogen synthase tion from the fed to the fasted state thereby explaining the (38.8 { 12.1 vs. 60.1 { 4.6 mU/mL hepatocytes) and glycopreferential use of fatty acids as a fuel in cirrhosis. 7 gen phosphorylase (127 { 19 vs. 178 { 33 U/mL hepato-
The mechanisms leading to reduced hepatic and skeletal cytes) were both reduced in BDL rats as were their cormuscle glycogen stores in animals and humans with cirrhosis responding active fractions (30 { 18 vs. 66 { 8% and 58 are not clear so far. Because of the complexity of its regula-{ 10 vs. 76 { 10). At this time point, the glycogen content tion, there are many possible mechanisms whereby glycogen in soleus muscle was decreased by 64% in BDL. The glumetabolism could be disturbed in humans or animals with cagon plasma concentration was increased in BDL rats cirrhosis. Glycogen synthase and phosphorylase are the two at both time points. There were positive correlations bekey enzymes responsible for glycogen synthesis and glycogentween the volume fraction and both hepatic glycogen olysis, respectively. The activities of these enzymes are concontent and total activity of hepatic glycogen synthase. trolled by phosphorylation and dephosphorylation as well Plasma glucagon and the active fraction of hepatic glyas by the abundance of metabolites or substrates such as cogen synthase were negatively correlated. The current glucose, glucose-6-phosphate, adenosine monophosphate, studies show a progressive decrease in the hepatic and adenosine diphosphate, phosphate, prostaglandins, and enskeletal muscle glycogen content in BDL rats. The obdotoxin. 9-15 Glycogen synthase is activated by dephosphorylaserved decrease in the activities of glycogen synthase tion and glycogen phosphorylase by phosphorylation. Phosand phosphorylase suggest that reduced glycogen synphorylation of glycogen synthase and dephosphorylation of thesis is the major mechanism leading to the reduction glycogen phosphorylase are under control of glycogenolytic in the hepatic glycogen content in BDL rats. (HEPATOLhormones such as catecholamines and glucagon, the latter OGY 1996;24:902-907.)
being effective in liver but not in skeletal muscle, which act by cyclic adenosine monophosphate-and/or Ca 2/ -dependent Patients with cirrhosis show a shift from the normally used mechanisms. [9][10][11] Inversely, the administration of insulin to carbohydrates to fatty acids as the preferred energy source experimental animals or isolated human hepatocytes leads to in the postabsorptive state, possibly as a consequence of alteractivation of glycogen synthase and deactivation of glycogen ations in glycogen metabolism. 1,2 Patients with alcohol-inphosphorylase. 9,10,15 duced cirrhosis have decreased hepatic glycogen stores 1 and Long-term bile duct ligation leads to progressive fibrosis and eventually cirrhosis 2 to 4 weeks after surgery. [16][17][18] In this animal model, which is both clinically and histologically comparable with extrahepatic cholestasis in humans, 19,20 Abbreviations: CCl4, carbon tetrachloride; BDL, bile duct ligation; AST, aspartate aminoearly studies using electron microscopy suggested a decrease transferase; ABT, aminopyrine breath test.