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In vivo and in silico dynamics of the development of Metabolic Syndrome
The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991635/ https://www.ncbi.nlm.nih.gov/pubmed/29879115 http://dx.doi.org/10.1371/journal.pcbi.1006145 |
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author | Rozendaal, Yvonne J. W. Wang, Yanan Paalvast, Yared Tambyrajah, Lauren L. Li, Zhuang Willems van Dijk, Ko Rensen, Patrick C. N. Kuivenhoven, Jan A. Groen, Albert K. Hilbers, Peter A. J. van Riel, Natal A. W. |
author_facet | Rozendaal, Yvonne J. W. Wang, Yanan Paalvast, Yared Tambyrajah, Lauren L. Li, Zhuang Willems van Dijk, Ko Rensen, Patrick C. N. Kuivenhoven, Jan A. Groen, Albert K. Hilbers, Peter A. J. van Riel, Natal A. W. |
author_sort | Rozendaal, Yvonne J. W. |
collection | PubMed |
description | The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available. |
format | Online Article Text |
id | pubmed-5991635 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-59916352018-06-16 In vivo and in silico dynamics of the development of Metabolic Syndrome Rozendaal, Yvonne J. W. Wang, Yanan Paalvast, Yared Tambyrajah, Lauren L. Li, Zhuang Willems van Dijk, Ko Rensen, Patrick C. N. Kuivenhoven, Jan A. Groen, Albert K. Hilbers, Peter A. J. van Riel, Natal A. W. PLoS Comput Biol Research Article The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available. Public Library of Science 2018-06-07 /pmc/articles/PMC5991635/ /pubmed/29879115 http://dx.doi.org/10.1371/journal.pcbi.1006145 Text en © 2018 Rozendaal et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Rozendaal, Yvonne J. W. Wang, Yanan Paalvast, Yared Tambyrajah, Lauren L. Li, Zhuang Willems van Dijk, Ko Rensen, Patrick C. N. Kuivenhoven, Jan A. Groen, Albert K. Hilbers, Peter A. J. van Riel, Natal A. W. In vivo and in silico dynamics of the development of Metabolic Syndrome |
title | In vivo and in silico dynamics of the development of Metabolic Syndrome |
title_full | In vivo and in silico dynamics of the development of Metabolic Syndrome |
title_fullStr | In vivo and in silico dynamics of the development of Metabolic Syndrome |
title_full_unstemmed | In vivo and in silico dynamics of the development of Metabolic Syndrome |
title_short | In vivo and in silico dynamics of the development of Metabolic Syndrome |
title_sort | in vivo and in silico dynamics of the development of metabolic syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991635/ https://www.ncbi.nlm.nih.gov/pubmed/29879115 http://dx.doi.org/10.1371/journal.pcbi.1006145 |
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