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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
- 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.
- Subjects :
- Liver/metabolism
computational modeling
APOE3
Systems Analysis
High-Fat/adverse effects
Bile Acids and Salts/metabolism
Apolipoprotein E3
SDG 3 – Goede gezondheid en welzijn
Diet, High-Fat
Bile Acids and Salts
Cholesterol/metabolism
Mice
SDG 3 - Good Health and Well-being
energy expenditure
CETP
Diet, High-Fat/adverse effects
Glucose/metabolism
bile acid
Animals
Longitudinal Studies
Metabolic Syndrome/genetics
Triglycerides
Metabolic Syndrome
Nutrition and Dietetics
Fatty Acids
cholesterol
metabolic syndrome
triglycerides
Apolipoprotein E3/genetics
Diet
Cholesterol Ester Transfer Proteins
Fatty Acids/metabolism
Cholesterol
Glucose
Phenotype
Liver
Cholesterol Ester Transfer Proteins/genetics
Food Science
Subjects
Details
- ISSN :
- 20726643
- Volume :
- 14
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Nutrients
- Accession number :
- edsair.doi.dedup.....2c0cd0d66ecfe9a0d37556a04d990ee3