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

被引:2
|
作者
Paalvast, Yared [1 ]
Zhou, Enchen [2 ,3 ]
Rozendaal, Yvonne J. W. [4 ]
Wang, Yanan [2 ,3 ]
Gerding, Albert [1 ]
van Dijk, Theo H. [1 ]
de Boer, Jan Freark [1 ]
Rensen, Patrick C. N. [2 ,4 ]
van Dijk, Ko Willems [3 ,5 ]
Kuivenhoven, Jan A. [1 ]
Bakker, Barbara M. [1 ]
van Riel, Natal A. W. [4 ,6 ]
Groen, Albert K. [1 ,6 ]
机构
[1] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, NL-9713 AV Groningen, Netherlands
[2] Leiden Univ, Dept Med, Div Endocrinol, Med Ctr, NL-2300 RC Leiden, Netherlands
[3] Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, NL-2300 RC Leiden, Netherlands
[4] Eindhoven Univ Technol, Dept Biomed Engn, NL-5600 MB Eindhoven, Netherlands
[5] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RC Leiden, Netherlands
[6] Univ Amsterdam, Lab Expt Vasc Med, Amsterdam UMC, NL-1105 AZ Amsterdam, Netherlands
关键词
computational modeling; cholesterol; bile acid; energy expenditure; metabolic syndrome; triglycerides; APOE3; CETP; HIGH-DENSITY-LIPOPROTEIN; BILE-ACIDS; ABSORPTION; MICROBIOTA; CIRRHOSIS; GUT;
D O I
10.3390/nu14224936
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
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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页数:15
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