Fig 1.
The porto-central axis of the sinusoid is considered to be the repeating unit of the liver. Cells and blood are compartmentalized into groups according to their position along the liver sinusoid. This allows the model to include changes in blood oxygenation, hormone concentrations and substrate and product concentrations across the sinusoid as well as differences in hepatic enzyme expression between compartments. Blood exits the sinusoid into a larger compartment representing the rest of the body. Blood in this compartment interacts with the pancreas, lungs and adipose tissue. Glucose and FFA inputs and consumption also occur in this compartment.
Fig 2.
Variables and conversions included in each hepatic compartment.
In addition to the hormonal regulation, almost all of the glucose and lipid metabolism conversions show some form of allosteric regulation. Lipolysis is also included but it occurs at very slow rate in hepatocytes.
Table 1.
The rate equations for the variables included in the hepatic compartments of the model.
Table 2.
The processes included in the model.
Fig 3.
(a) The effects of simulating IR on total hepatic metabolism (averaged across the sinusoid). (b) The heterogeneity in the effects of simulating IR across the sinusoid. (c) The effects of simulating increasing severities of IR on plasma triglyceride, glucose and FFA concentrations compared with experimental data from Sindelka et al [65] and Burnt et al. [66].
Fig 4.
Metabolite concentrations when simulating NAFLD.
(a) The average triglyceride (b) FFA, (c) ATP, (d) glycerol-3-phosphate and (e) glycogen concentration and (f) the difference between postprandial peak and pre-prandial trough glycogen concentrations in the different regions of the sinusoid when simulating (purple) a MH individual, (orange) IR alone and (red) IR with increase SREBP-1c expression using a moderate intake diet.
Fig 5.
Metabolic rates when simulating NAFLD.
The average rates of (a) triglyceride synthesis, (b) lipolysis, (c) triglyceride release as VLDL, (d) β-oxidation (e) FFA uptake, (f) lipogenesis and (g) ATP synthesis from acetyl-CoA in the different regions of the sinusoid when simulating (purple) a MH individual, (orange) IR alone and (red) IR with increase SREBP-1c expression using a moderate intake diet.
Fig 6.
The simulated effects of varying dietary intake in the model.
(a-d) The average hepatic lipid content across the sinusoid when simulating varying glucose and FFA intake diets in individuals with (a) MH insulin sensitivity (100%, KIR = 1), (b) developing IR (5%, KIR = 0.05), (c) severe IR (1.5%, KIR = 0.015) and (d) severe IR in combination with increased SREBP-1c expression. (e-f) The effects of high fat and carbohydrate (glucose) intake on (e) ATP concentrations and (f) FFA concentrations across the sinusoid when simulating a MH, insulin sensitive individual. High and low intakes correspond to a sustained 12.5% difference in intake relative to the moderate intake det. Very high and raised intakes correspond to 25% and 5% increases respectively. The average concentrations over a 4 hours intake/output cycle are depicted.
Table 3.
The effect of varying the baseline rate constants, vb, for the various hepatic metabolism processes included in the model on cellular and plasma FFA and triglyceride concentrations.
Table 4.
The effect of altering the zonation constants kn of lipid metabolism processes on steatosis location (compartment1: compartment 8 triglyceride ratio) when simulating for IR patients on a moderate diet.