Abstract
BackgroundAdaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. Here, we used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis.ResultsModel simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that control of the hepatic glucose metabolism is mainly exerted by enzymes alone, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects.ConclusionIn hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0237-6) contains supplementary material, which is available to authorized users.
Highlights
Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters
The literature data used for the parametrization and validation of the model were obtained from liver tissue or hepatocytes of rats that have adopted different physiological states owing to either nutritional, genetic, or chemical interventions
These animals are moderately obese and display elevated plasma glucose levels compared to rats in the normal state kept under well-controlled feeding
Summary
Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. An important feature of cellular metabolic networks is their ability to adjust the functional output to largely varying external conditions such as changes in nutrient supply, enforced synthesis of macromolecules during the growth phase, varying hormone levels, or presence of toxins. This adjustment is achieved by diverse regulatory mechanisms tuning the activities of enzymes and transporters in a. A second fundamental regulatory concept, usually termed kinetic regulation, consists of changes in the specific activity of enzymes due to conformational changes of the protein structure This allows a rapid adaptation of the network to varying external and internal conditions within a few seconds. Only specific key enzymes carry the burden of the regulatory control
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