A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism
Fig 1
Schematic model representation (A) model of carbohydrate metabolism describing glycolysis, glyconeogenesis and glycogen synthesis and utilization. The model describes the enzymes Glucokinase (GK), Glucose-6-phosphate isomerase (GPI), Phosphofructokinase 1 (PFK1), Aldolase (ALD), Triosephosphate isomerase (TPI), Glyceraldehydephosphate dehydrogenase (GAPDH), Phosphoglycerate kinase (PGK), Phosphoglycerate mutase (PGM), Enolase (EN), Pyruvate kinase (PK) Lactate dehydrogenase (LDH), Glucose-6-phosphate phosphatase (G6P), Phosphofructokinase 2 (PFK2), Fructose-2,6-bisphosphatase (FBP2), Fructose-1,6-bisphosphatase (FBP1), Phosphoenolpyruvate carboxykinase (PEPCK), Pyruvate carboxylase (PC), Nucleoside-diphosphate kinase (NDK), Malate dehydrogenase (MDH), Pyrophosphatase (PPASE), Glucose-1-phosphate isomerase (P1PI), Glycuronosyltransferase (UGT), Glycogen phosphorylase (GP), Glycogen synthase (GS) and transporters (ER <-> cytosol: Glucose-6-phosphate transporter (Glc6PT), Glucose transporter (GlcT); mitochondrion <-> cytosol: Pyruvate transporter (PYRT), Phosphoenolpyruvate transporter (PEPT), Malate transporter (MALT); extern <-> cytosol: Glucose transporter 2 (GLUT2), Lactate transporter (LACT). Enzymes that are phosphorylated or dephosphorylated in response to insulin (Ins) and glucagon (Glu) stimulus are marked by a yellow P, allosteric modification of enzymes is marked by a red A. The model contains the metabolites: glucose (Glc), glucose-6-phosphate (Glc6P), fructose-6-phosphate (Fru6P), fructose-1,6-bisphosphate (Fru16P2), glyceraldehydephosphate (GraP), dihydroxyacetonephosphate (DHAP), 1,3-bisphosphoglycerate (13P2G), 3-phosphoglycerate (3PG), 2-phosphoglycerate (2PG), phosphoenolpyruvate (PEP), pyruvate (Pyr), lactate (Lac), malate (Mal), oxaloacetate (OA), glucose-1-phosphate (Glc1P), UDP-glucose (UDP-glc), glycogen, fructose-2,6-bisphosphate (Fru26P2). The cofactors NADH, NAD, ATP, ADP, phosphate, UTP and UDP are not treated as dynamic variables. All physiological metabolites produced or consumed in the hepatocyte during glycolysis and gluconeogenesis are comprised into lactate. Reproduced from [23], adapted from [67]. (B) sinusoidal unit describing blood flow, nutrient and hormone distribution within the sinusoids. The model encompasses the blood vessel, the adjacent space of Disse and the surrounding hepatocyte cell layer. It is described by morphological parameters (blood vessel radius, thickness of the space of Disse, hepatocyte thickness, hepatocyte number, sinusoid length, degree of fenestration) and systemic parameters (central and portal vein hydrostatic pressure, plasma and lympgh oncotic pressure, diffusion coefficients).