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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9698005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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