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).
Highlights
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
They are catalyzed by specific enzymes and transport proteins that are regulated in multiple ways by their immediate ligands, allosteric effectors, hormone-dependent reversible phosphorylation, and variable gene expression
Their average contribution is indirectly contained in the fitted Vmax values
Summary
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. Chemical reactions and mass transport are the basic processes in a metabolic network They are catalyzed by specific enzymes and transport proteins that are regulated in multiple ways by their immediate ligands, allosteric effectors, hormone-dependent reversible phosphorylation, and variable gene expression. Decrease of malonyl-CoA concentration during the overnight fast is lifesaving because activation of CPT enables the enhanced oxidation of fatty acids to acetyl CoA and the formation of glucose-sparing ketone bodies in the liver[2] This example underlines the importance of biochemistry-based kinetic models that incorporate such important regulatory features of enzymes. Using quantitative proteomics data for the scaling of maximal enzyme activities, the model opens the goal for a quantitative functional interpretation of gene expression changes We applied this approach to reveal the patient-specific metabolic profile of adenoma and HCC. Our model provides a powerful tool for computational studies of liver metabolism in health and disease
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