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A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice d...

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Autores principales: Paalvast, Yared, Zhou, Enchen, Rozendaal, Yvonne J. W., Wang, Yanan, Gerding, Albert, van Dijk, Theo H., de Boer, Jan Freark, Rensen, Patrick C. N., van Dijk, Ko Willems, Kuivenhoven, Jan A., Bakker, Barbara M., van Riel, Natal A. W., Groen, Albert K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698005/
https://www.ncbi.nlm.nih.gov/pubmed/36432620
http://dx.doi.org/10.3390/nu14224936
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author Paalvast, Yared
Zhou, Enchen
Rozendaal, Yvonne J. W.
Wang, Yanan
Gerding, Albert
van Dijk, Theo H.
de Boer, Jan Freark
Rensen, Patrick C. N.
van Dijk, Ko Willems
Kuivenhoven, Jan A.
Bakker, Barbara M.
van Riel, Natal A. W.
Groen, Albert K.
author_facet Paalvast, Yared
Zhou, Enchen
Rozendaal, Yvonne J. W.
Wang, Yanan
Gerding, Albert
van Dijk, Theo H.
de Boer, Jan Freark
Rensen, Patrick C. N.
van Dijk, Ko Willems
Kuivenhoven, Jan A.
Bakker, Barbara M.
van Riel, Natal A. W.
Groen, Albert K.
author_sort Paalvast, Yared
collection PubMed
description Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.
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spelling pubmed-96980052022-11-26 A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding Paalvast, Yared Zhou, Enchen Rozendaal, Yvonne J. W. Wang, Yanan Gerding, Albert van Dijk, Theo H. de Boer, Jan Freark Rensen, Patrick C. N. van Dijk, Ko Willems Kuivenhoven, Jan A. Bakker, Barbara M. van Riel, Natal A. W. Groen, Albert K. Nutrients Article Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice. MDPI 2022-11-21 /pmc/articles/PMC9698005/ /pubmed/36432620 http://dx.doi.org/10.3390/nu14224936 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Paalvast, Yared
Zhou, Enchen
Rozendaal, Yvonne J. W.
Wang, Yanan
Gerding, Albert
van Dijk, Theo H.
de Boer, Jan Freark
Rensen, Patrick C. N.
van Dijk, Ko Willems
Kuivenhoven, Jan A.
Bakker, Barbara M.
van Riel, Natal A. W.
Groen, Albert K.
A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title_full A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title_fullStr A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title_full_unstemmed A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title_short A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
title_sort systems analysis of phenotype heterogeneity in apoe*3leiden.cetp mice induced by long-term high-fat high-cholesterol diet feeding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698005/
https://www.ncbi.nlm.nih.gov/pubmed/36432620
http://dx.doi.org/10.3390/nu14224936
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