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The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling
BACKGROUND: Adaptation 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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774192/ https://www.ncbi.nlm.nih.gov/pubmed/26935066 http://dx.doi.org/10.1186/s12915-016-0237-6 |
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author | Bulik, Sascha Holzhütter, Hermann-Georg Berndt, Nikolaus |
author_facet | Bulik, Sascha Holzhütter, Hermann-Georg Berndt, Nikolaus |
author_sort | Bulik, Sascha |
collection | PubMed |
description | BACKGROUND: Adaptation 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. RESULTS: Model 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. CONCLUSION: In 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 MATERIAL: The online version of this article (doi:10.1186/s12915-016-0237-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4774192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-47741922016-03-03 The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling Bulik, Sascha Holzhütter, Hermann-Georg Berndt, Nikolaus BMC Biol Research Article BACKGROUND: Adaptation 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. RESULTS: Model 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. CONCLUSION: In 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 MATERIAL: The online version of this article (doi:10.1186/s12915-016-0237-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-03-02 /pmc/articles/PMC4774192/ /pubmed/26935066 http://dx.doi.org/10.1186/s12915-016-0237-6 Text en © Bulik et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Bulik, Sascha Holzhütter, Hermann-Georg Berndt, Nikolaus The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title | The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title_full | The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title_fullStr | The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title_full_unstemmed | The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title_short | The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
title_sort | relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774192/ https://www.ncbi.nlm.nih.gov/pubmed/26935066 http://dx.doi.org/10.1186/s12915-016-0237-6 |
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