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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

Authors :
Yared Paalvast
Enchen Zhou
Yvonne J. W. Rozendaal
Yanan Wang
Albert Gerding
Theo H. van Dijk
Jan Freark de Boer
Patrick C. N. Rensen
Ko Willems van Dijk
Jan A. Kuivenhoven
Barbara M. Bakker
Natal A. W. van Riel
Albert K. Groen
Center for Liver, Digestive and Metabolic Diseases (CLDM)
Computational Biology
EAISI Health
Systems Biology and Metabolic Disease
Eindhoven MedTech Innovation Center
Experimental Vascular Medicine
ACS - Microcirculation
Amsterdam Gastroenterology Endocrinology Metabolism
ACS - Diabetes & metabolism
ACS - Atherosclerosis & ischemic syndromes
Molecular Cell Physiology
AIMMS
Source :
Nutrients; Volume 14; Issue 22; Pages: 4936, Nutrients, 14(22):4936. MDPI AG, Nutrients, 14(22):4936. Multidisciplinary Digital Publishing Institute (MDPI), Nutrients, 14(22). MDPI
Publication Year :
2022

Abstract

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.

Details

ISSN :
20726643
Volume :
14
Issue :
22
Database :
OpenAIRE
Journal :
Nutrients
Accession number :
edsair.doi.dedup.....2c0cd0d66ecfe9a0d37556a04d990ee3