HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology

Abstract

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

Genetic determinants of steatosis and fibrosis progression in paediatric non‐alcoholic fatty liver disease

“…Metabolic implication of GCKR, UCP2 (A‐C, Model: Ref. ) and PNPLA3 (D, Model: Ref. ) polymorphism on hepatic metabolism.…”

“…We simulated stimulus implications of GCKR, UCP2 and PNPLA3 polymorphisms on hepatic glucose and fat metabolism with a metabolic model of central hepatic metabolism and hepatic lipid droplet metabolism. 19,20 Please refer to Methods S1 for full details. For all simulations, we used MATLAB release 2012a (The MathWorks, Inc, Natick, MA).…”

Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes

“…In 2019, the virtual metabolic human database has been presented to facilitate computational modeling by linking genome-scale networks of human metabolism to diseases and nutrition (3). On the other hand, multi-scale, largescale dynamic models have been extensively developed for human metabolism (4)(5)(6)(7)(8)(9)(10)(11). A virtual metabolic human model is highly expected as a core model toward the virtual physiological human.…”

“…Since those compartment models were the coarse-grained models, their applications were limited to an understanding of the specific functions. To overcome this limitation, biochemistry-based models were constructed that assigned a rate equation to each metabolic reaction within a cell of liver and skeletal muscle while considering allosteric effectors, enzyme activity regulation, and hormone-dependent reversible phosphorylation (5,6,11). The kinetics were measured by means of in vitro assays.…”

Metabolic modelling of kidney diseases: Lessons learned from the liver

“…This may fuel cortical cells with lactate formed by medullary cells as glycolytic product. 38 Owing to the high similarities shared between the central metabolism of hepatocytes and renal tubule cells, re-parameterization of complex kinetic liver models 14 with kidney-specific parameters, as has been done in Ref. 39 , represents an efficient way to generate metabolic cell models that can be integrated into existing tissue-scale models of the kidney.…”