Figure 1.
Liver glycogen levels control circuit architecture.
Glycogen is synthesized by GSa and broken down into glucose-6-phosphate by GPa. Glycogen levels within the liver are shown in the Fed, Fasting and Fasted state as shaded boxes, with full liver glycogen stores being shown as a solid black box in the Fed portion of the circuit. Arrows indicate which branch of the pathway is active. Substrate cycling occurs in the glycogen-depleted (empty box), Fasted state.
Figure 2.
Diagrammatic representation of key features of the physiological model.
The general design principles of the model are based on established bioenergetic physiology [1]. The liver, placed at the center of this diagrammatic representation of “the body”, contains the glycogen circuitry which lies within hepatocytes connected to other organs by the vascular system (show in red). Blood within the vascular system travels around the body, carrying materials between the liver and other organs, with a cycle time of about one minute. Key: Gluc = glucose; FFA = free fatty acids; Ket = ketones; TAG = triacylglycerol; ACoA = acetyl CoA; Alan = alanine. Note that kidney, brain and erythrocytes are not included in the current model.
Figure 3.
Simulation results: dynamic responses of selected hormones and substrates during a 24-hour fasting period.
Note that hormone and substrate concentrations are normalized by their maximum values during the simulation. Blood glucose concentration has a multiplier of 0.8 to give a better view. Key: bl gluc = blood glucose; pl glucagon = plasma glucagon; pl ins = plasma insulin; pl FFA = plasma free fatty acids; bl ket = blood ketone bodies.
Figure 4.
The central control glycogen circuitry (modified from Figure 3.1 in [43]).
Rectangles and circles enclose the names or abbreviations of enzymes and substrates accordingly. The reactions as a result of an increase in cAMP concentrations are shown with bold arrows. cAMP = cyclic adenosine monophosphate; R2C2 = cAMP dependent protein kinase; C = R2C2 catalytic subunit; PKb = inactive phosphorylase kinase; PKa = active phosphorylase kinase; GPb = inactive glycogen phosphorylase; GPa = active glycogen phosphorylase; GSb = inactive glycogen phosphorylase; GSb = inactive glycogen synthase; GSa = active glycogen synthase; P = phosphate; g-6-p = glucose-6-phosphate; PP1, protein phosphatase-1.
Figure 5.
Fractional activation of GPa and GSa plotted against blood glucose concentration under two selected
. A:
corresponds to a stronger binding between glycogen phosphorylase a (GPa) and GS phosphatase, which results in a strong inhibition on the activation of glycogen synthase (GSa). B:
corresponds to a weaker binding between GPa and GS phosphatase, where the inhibition by GPa is partially relieved.
Figure 6.
Time evolutions curves of selected enzymes and substrates.
A: Time response curves of GSa and GPa under two selected after glucose stimulus enters blood stream at
in a glycogen depleted liver. Crossover of GSa and GPa occurs at 13.4 and 30.6 minutes respectively. B: Liver glycogen concentration plotted against time under the two selected
.
Figure 7.
Enzymes and substrate responses over a series of
ranging from
to
. A: System response time to glucose stimulus plotted against
in a glycogen depleted liver. Blue: system response time defined by the cross-over point of glycogen synthase a (GSa) and glycogen phosphorylase a (GPa). Black: system response time defined by the time when liver glycogen concentration exceeds 0.5 mM. Note that the difference in system response time is about 30 mins for the lowest and highest values of
selected here under both definitions. B: The co-activated percentage of GSa and GPa at the cross-over point as a function of
. Note that this percentage represents the maximum co-active percentage of both enzymes, hence it is an indicator of the level of substrate cycling in the system. The points inside the rectangles (
) and triangles (
) are the two values chosen in Figure 6.
Figure 8.
Previous experimental results by Hue et al.
Glycogen phosphorylase a (GPa) and glycogen synthase a (GSa) activities in hepatocytes under fed (A) and fasted conditions (B) are redrawn from experimental results by Hue et al. [49]). From left to right, top to bottom in panel A and B: 4 increasing glucose concentrations from 5.5 to 55 mM in the incubation medium caused a sequential inactivation of glycogen phosphorylase and activation of glycogen synthase.
Figure 9.
Simulation results by computational modeling (a parallel comparison to Figure 8).
Glycogen synthase a (solid circles) and glycogen phosphorylase a (open circles) activities are plotted against time under 4 different glucose input rate in fed (A) and fasted livers (B). From left to right, top to bottom: . Note that the y-axis is the active to total enzyme percentage.