Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism Kinetic Model of Human Hepatic Glucose Metabolism Authors Matthias Koenig, Sascha Bulik and Hermann-Georg Holzhuetter Corresponding Author Matthias Koenig matthias.koenig@charite.de Charite Berlin, Computational Systems Biochemistry, Germany Keywords hepatic glucose metabolism; kinetic model; glucose homeostasis; liver Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present, a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in excellent agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from hepatic glucose production under hypoglycemia to hepatic glucose utilization under hyperglycemia essential for glucose homeostasis. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. Compartments Id Name Dimension Constant SBO GO cyto cytosol 3 Y SBO:0000290 physical compartment GO:0005829 cytosol blood blood 3 Y SBO:0000290 physical compartment GO:0005615 extracellular space mito mitochondrion 3 Y SBO:0000290 physical compartment GO:0005739 mitochondrion mm mitochondrial membrane 2 Y SBO:0000290 physical compartment GO:0031966 mitochondrial membrane pm plasma membrane 2 Y SBO:0000290 physical compartment GO:0005886 plasma membrane Species Id Name Compartment Constant Init [mM] KEGG CHEBI UNIPROT SBO atp ATP cyto Y 2.8 KEGG:C00002 CHEBI:15422 SBO:0000299 metabolite adp ADP cyto Y 0.8 KEGG:C00008 CHEBI:16761 SBO:0000299 metabolite amp AMP cyto Y 0.16 KEGG:C00020 CHEBI:16027 SBO:0000299 metabolite utp UTP cyto N 0.27 KEGG:C00075 CHEBI:15713 SBO:0000299 metabolite udp UDP cyto N 0.09 KEGG:C00015 CHEBI:17659 SBO:0000299 metabolite gtp GTP cyto N 0.29 KEGG:C00044 CHEBI:15996 SBO:0000299 metabolite gdp GDP cyto N 0.10 KEGG:C00035 CHEBI:17552 SBO:0000299 metabolite nad NAD+ cyto Y 1.22 KEGG:C00003 CHEBI:15846 SBO:0000299 metabolite nadh NADH cyto Y 5.60E-004 KEGG:C00004 CHEBI:16908 SBO:0000299 metabolite p phosphate cyto Y 5 KEGG:C00009 SBO:0000299 metabolite pp pyrophosphate cyto N 0.008 KEGG:C00013 SBO:0000299 metabolite h2o H2O cyto Y 55000 KEGG:C00001 CHEBI:15377 SBO:0000299 metabolite co2 CO2 cyto Y 5 KEGG:C00011 CHEBI:16526 SBO:0000299 metabolite h H+ cyto Y 5.00E-008 KEGG:C00080 CHEBI:24636 SBO:0000299 metabolite glc1p glucose-1-phosphate cyto N 0.012 KEGG:C00103 CHEBI:16077 SBO:0000299 metabolite udpglc UDP-glucose cyto N 0.38 KEGG:C00029 CHEBI:18066 SBO:0000299 metabolite glc glucose cyto N 5 KEGG:C00031 CHEBI:4167 SBO:0000299 metabolite glyglc glycogen cyto N 250 KEGG:C00182 CHEBI:28087 SBO:0000299 metabolite fru6p fructose-6-phosphate cyto N 0.05 KEGG:C00085 CHEBI:15946 SBO:0000299 metabolite glc6p glucose-6-phosphate cyto N 0.12 KEGG:C00092 CHEBI:4170 SBO:0000299 metabolite fru26bp fructose-2,6-bisphospate cyto N 0.004 KEGG:C00665 CHEBI:28602 SBO:0000299 metabolite fru16bp fructose-1,6-bisphospate cyto N 0.02 KEGG:C00354 CHEBI:16905 SBO:0000299 metabolite dhap dihydroxyacetone phosphate cyto N 0.03 KEGG:C00111 CHEBI:16108 SBO:0000299 metabolite grap glyceraldehyde 3-phosphate cyto N 0.1 KEGG:C00118 CHEBI:29052 SBO:0000299 metabolite pg3 3-phosphoglycerate cyto N 0.27 KEGG:C00197 CHEBI:17794 SBO:0000299 metabolite bpg13 1,3-bisphospho-glycerate cyto N 0.3 KEGG:C00236 CHEBI:16001 SBO:0000299 metabolite pep phosphoenolpyruvate cyto N 0.15 KEGG:C00074 CHEBI:44897 SBO:0000299 metabolite pg2 2-phosphoglycerate cyto N 0.03 KEGG:C00631 CHEBI:17835 SBO:0000299 metabolite oaa oxaloacetate cyto N 0.01 KEGG:C00036 CHEBI:30744 SBO:0000299 metabolite pyr pyruvate cyto N 0.1 KEGG:C00022 CHEBI:32816 SBO:0000299 metabolite glc_blood glucose blood Y 5 KEGG:C00031 CHEBI:4167 SBO:0000299 metabolite lac lactate cyto N 0.5 KEGG:C00186 CHEBI:422 SBO:0000299 metabolite p_mito phosphate mito Y 5 KEGG:C00009 SBO:0000299 metabolite oaa_mito oxaloacetate mito N 0.01 KEGG:C00036 CHEBI:30744 SBO:0000299 metabolite lac_blood lactate blood Y 1.2 KEGG:C00186 CHEBI:422 SBO:0000299 metabolite co2_mito CO2 mito Y 5 KEGG:C00011 CHEBI:16526 SBO:0000299 metabolite pyr_mito pyruvate mito N 0.1 KEGG:C00022 CHEBI:32816 SBO:0000299 metabolite cit_mito citrate mito Y 0.32 KEGG:C00158 CHEBI:30769 SBO:0000299 metabolite pep_mito pep mito N 0.15 KEGG:C00074 CHEBI:44897 SBO:0000299 metabolite acoa_mito acetyl-coenzyme A mito Y 0.04 KEGG:C00024 CHEBI:15351 SBO:0000299 metabolite gtp_mito GTP mito N 0.29 KEGG:C00044 CHEBI:15996 SBO:0000299 metabolite gdp_mito GDP mito N 0.10 KEGG:C00035 CHEBI:17552 SBO:0000299 metabolite atp_mito ATP mito Y 2.8 KEGG:C00002 CHEBI:15422 SBO:0000299 metabolite adp_mito ADP mito Y 0.8 KEGG:C00008 CHEBI:16761 SBO:0000299 metabolite nad_mito NAD+ mito Y 0.98 KEGG:C00003 CHEBI:15846 SBO:0000299 metabolite h_mito H+ mito Y 1.00E-008 KEGG:C00011 CHEBI:24636 SBO:0000299 metabolite coa_mito coenzymeA mito Y 0.055 KEGG:C00010 CHEBI:15346 SBO:0000299 metabolite nadh_mito NADH mito Y 0.24 KEGG:C00004 CHEBI:16908 SBO:0000299 metabolite epinephrine_blood epinephrine blood N 206.11 KEGG:C00547 CHEBI:18357 SBO:0000299 metabolite glucagon_blood glucagon blood N 4.36E-008 KEGG:C01501 UNIPROT:P01275 SBO:0000299 metabolite insulin_blood insulin blood N 7.61E-008 KEGG:C00723 UNIPROT:P01308 SBO:0000299 metabolite h20_mito H2O mito Y 55000 KEGG:C00080 CHEBI:15377 SBO:0000299 metabolite Reactions Id Name Compartment Irreversible Vmax [µmol/kg/min] EC KEGG UNIPROT SBO GLUT2 GLUT2 glucose transporter (facilitated diffusion) pm N 420 UNIPROT:P11168 SBO:0000284 transporter GK Glucokinase, hexokinase IV cyto Y 25.2 EC:2.7.1.2 KEGG:R00299 UNIPROT:P35557 SBO:0000014 enzyme G6PASE Glucose-6-phosphatase cyto Y 18.9 EC:3.1.3.9 KEGG:R00303 UNIPROT:P35575 SBO:0000014 enzyme GPI Glucose-6-phosphate isomerase cyto N 420 EC:5.3.1.9 KEGG:R00771 UNIPROT:P06744 SBO:0000014 enzyme G16PI glucose-1-phosphate 1,6-phosphomutase cyto N 100 EC:5.4.2.2 KEGG:R00959 UNIPROT:P36871, UNIPROT:Q96G03 SBO:0000014 enzyme UPGASE UTP:Glucose-1-phosphate uridylyltransferase cyto N 80 EC:2.7.7.9 KEGG:R00289 UNIPROT:Q16851 SBO:0000014 enzyme PPASE Pyrophosphate phosphohydrolase cyto Y 2.4 EC:3.6.1.1 KEGG:R00004 UNIPROT:Q15181 SBO:0000014 enzyme GS Glycogen synthase cyto Y 13.2 UNIPROT:P54840 SBO:0000014 enzyme GP Glycogen phosphorylase cyto N 6.8 UNIPROT:P06737 SBO:0000014 enzyme NTKGTP Nucleosid diphosphate kinase (GTP) cyto N 0 EC:2.7.4.6 KEGG:R00330 SBO:0000014 enzyme NTKUTP Nucleosid diphosphate kinase (UTP) cyto N 2940 EC:2.7.4.6 KEGG:R00156 SBO:0000014 enzyme AK Adenylat kinase cyto N 0 EC:2.7.4.3 KEGG:R00127 SBO:0000014 enzyme PFK2 Phosphofructo kinase 2 cyto Y 0.0042 EC:2.7.1.105 KEGG:R02732 UNIPROT:P16118 SBO:0000014 enzyme FBP2 Fructose-2,6-bisphosphatase cyto Y 0.126 EC:3.1.3.46 KEGG:R02731 UNIPROT:P16118 SBO:0000014 enzyme PFK1 Phosphofructo kinase 1 cyto Y 7.182 EC:2.7.1.11 KEGG:R00756 UNIPROT:P17858 SBO:0000014 enzyme FBP1 Fructose-1,6-bisphosphatase cyto Y 4.326 EC:3.1.3.11 KEGG:R00762 UNIPROT:O00757, UNIPROT:P09467 SBO:0000014 enzyme TPI Triosephosphate isomerase cyto N 420 EC:5.3.1.1 KEGG:R01015 UNIPROT:P60174 SBO:0000014 enzyme ALD Aldolase cyto N 420 EC:4.1.2.13 KEGG:R01068 UNIPROT:P05062 SBO:0000014 enzyme PGK Phosphoglycerate kinase cyto N 420 EC:2.7.2.3 KEGG:R01512 UNIPROT:P00558 SBO:0000014 enzyme GAPDH Glyceraldehydephosphate dehydrogenase cyto N 420 EC:1.2.1.12 KEGG:R01061 UNIPROT:P04406 SBO:0000014 enzyme EN Enolase cyto N 35.994 EC:4.2.1.11 KEGG:R00658 UNIPROT:P06733, UNIPROT:P09104, UNIPROT:P13929 SBO:0000014 enzyme PGAM 3-Phosphoglycerate mutase cyto N 420 EC:5.4.2.1 KEGG:R01518 UNIPROT:P18669 SBO:0000014 enzyme PEPCK Phosphoenolpyruvate carboxykinase cyto N 0 EC:4.1.1.32 KEGG:R00431 UNIPROT:P35558 SBO:0000014 enzyme PK Pyruvate kinase cyto Y 46.2 EC:2.7.1.40 KEGG:R00200 UNIPROT:P30613 SBO:0000014 enzyme PC Pyruvate Carboxylase mito Y 168 EC:6.4.1.1 KEGG:R00344 UNIPROT:P11498 SBO:0000014 enzyme PEPCK_mito Phosphoenolpyruvate carboxykinase mito N 546 EC:4.1.1.32 KEGG:R00431 UNIPROT:Q16822 SBO:0000014 enzyme LACT Lactate transporter pm N 5.418 SBO:0000284 transporter LDH Lactate dehydrogenase cyto N 12.6 EC:1.1.1.27 -KEGG:R00703 UNIPROT:P00338, UNIPROT:P07195, UNIPROT:P07864 SBO:0000014 enzyme PEPT PEP transporter mm N 33.6 SBO:0000284 transporter PYRT Pyruvate transporter mm N 42 SBO:0000284 transporter CS Citrate synthase mito N 4.2 EC:2.3.3.1 -KEGG:R00351 UNIPROT:O75390 SBO:0000014 enzyme PDH Pyruvate dehydrogenase mito Y 13.44 EC:1.2.4.1 KEGG:R00209 UNIPROT:P08559, UNIPROT:P11177, UNIPROT:P10515, UNIPROT:P09622, O00330 SBO:0000014 enzyme ACOAFLX Acetyl-CoA flux mito N 0 SBO:0000014 enzyme VCITFLX Citrate flux mito N 0 SBO:0000014 enzyme NDK_mito Nucleosid diphosphate kinase (GTP) mito N 420 EC:2.7.4.6 KEGG:R00330 SBO:0000014 enzyme OAAFLX Oxalacetate flux mito N 0 SBO:0000014 enzyme