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chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
been implicated in insulin-mediated activation of glycogen
synthase.
Live r
In liver, glycogen serves as the immediate glucose re-
serve for other tissues, and regulation of its metabolism
is closely linked to maintenance of blood glucose con-
centration. An important feature of glucose transport in
hepatocytes is its bidirectional flux across the plasma
membrane that is mediated by glucose transporter GLUT2.
Insulin does not regulate GLUT2 and its function is not
rate limiting. Therefore, the concentrations of glucose in
the blood and hepatocytes are equal. During energy depri-
vation for short periods of time such as overnight fasting,
moderate exercise, and stress, which cause hypoglycemia
(e.g., hypovolemic shock), glycogenolysis is stimulated.
During sustained periods of starvation, gluconeogenesis
maintains blood glucose homeostasis. During refeeding,
hepatocytes replenish their stores of glycogen by using
glucose-
6
-phosphate obtained from either plasma glucose
or from the gluconeogenic pathway using amino acids,
glycerol, and propionate as precursors. Regulatory fac-
tors include glucagon, vasopressin, angiotensin II, and
a-adrenergic agonists (including epinephrine). Glycogen
synthesis is stimulated by a rise in insulin or blood glucose
concentration.
C o n tro l o f G lycogen S yn th a se
Hepatic glycogen synthase is similar to the muscle en-
zyme, although it is encoded by different genes. It is inac-
tivated by phosphorylation and activated by d├ęphosphory-
lation and may contain
1 2
mol of alkali-labile phosphate
per mole of subunit. The phosphorylation sites have not
been mapped, and the specificities of hepatic glycogen
synthase kinases are not known.
Several enzymes that phosphorylate glycogen synthase
(muscle or liver)
in vitro
have been identified in liver.
cAMP-dependent protein kinase, thought to mediate the
inhibition of glycogen synthesis by glucagon, is simi-
lar to the muscle enzyme. A Ca
2
+/calmodulin-dependent
protein kinase may mediate Ca2+-dependent inactiva-
tion of the synthase by vasopressin, angiotensin II, and
a-adrenergic agonists. Casein kinase I and GSK-3 have
also been found in liver, and there are undoubtedly other
hepatic glycogen synthase kinases. As in muscle, hepatic
phosphorylase kinase is probably not important as a glyco-
gen synthase kinase
in vivo,
despite its ability to readily
phosphorylate the synthase
in vitro.
Muscle and liver thus
have major regulatory pathways in common but differ in
more subtle aspects of control.
Protein phosphatases-1,2A, 2B, and 2C occur in mam-
malian liver and, as in skeletal muscle, possess essentially
all of the phosphatase activity toward enzymes and reg-
ulatory proteins of glycogen metabolism. In liver, how-
ever, the ratios of the activities of phosphatase-2A and
2
C to that of phosphatase
- 1
are seven-fold higher than in
muscle. Although protein phosphatase-I sediments with
glycogen particles in both tissues, a much smaller fraction
is glycogen-associated in liver than in muscle. The specific
activity of phosphatase-2B is lower in liver than in muscle.
Protein phosphatase inhibitors-1 and 2 have been identi-
fied in liver, where they appear to function as they do in
muscle. A disinhibitor protein (M.W. ~9,000) of liver can
block the effects of inhibitors
- 1
and
2
on phosphatase-
1
.
C o n tro l o f G lyco g en P h o sp h o ryla se
Liver glycogen phosphorylase exists in an inactive, de-
phosphorylated form and in at least one active, phospho-
rylated form. Conversion of phosphorylase b to phospho-
rylase a is catalyzed by phosphorylase kinase, which is
activated by vasopressin, angiotensin II, and a-adrenergic
agonists (mediated by Ca2+) and by glucagon (which ele-
vates cAMP). Glucagon activation of phosphorylase is in
some way antagonized by insulin.
Dephosphorylation of glycogen phosphorylase a is
probably catalyzed by either protein phosphatase
- 1
or
2
A.
Binding of free glucose to phosphorylase a makes it a bet-
ter substrate for the phosphatase, increasing the rate of
inactivation of glycogenolysis. Phosphorylase a is a com-
petitive inhibitor of the reaction between glycogen syn-
thase b and phosphatase, suggesting that the same enzyme
dephosphorylates the synthase and kinase, activating one
and inhibiting the other.
In teg ra ted R eg u la tio n o f L iv e r G lycogen M etabolism
Glycogen metabolism in liver is regulated by phos-
phorylation and dephosphorylation of regulatory and
metabolic enzymes. Control of the phosphorylation state
is mediated by Ca2+, cAMP, cytosolic glucose concen-
tration, and perhaps, in the case of insulin, by another
mechanism.
When the glucose concentration rises in the h├ępato-
cyte, the rate of conversion of glycogen phosphorylase
a to phosphorylase b increases. This decreases the rate of
glycogenolysis and, initially, causes no change in glyco-
gen synthesis. As the concentration of phosphorylase a
falls, however, its ability to competitively inhibit glyco-
gen synthase b dephosphorylation decreases. The rate of
activation of glycogen synthase then increases, as does the
rate of synthesis of glycogen. Glucose can be an effective
regulator because its concentration in the hepatocyte varies
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