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

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  • Additional Information
    • Source:
      Publisher: MDPI Publishing Country of Publication: Switzerland NLM ID: 101521595 Publication Model: Electronic Cited Medium: Internet ISSN: 2072-6643 (Electronic) Linking ISSN: 20726643 NLM ISO Abbreviation: Nutrients Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI Publishing
    • Subject Terms:
      Cholesterol Ester Transfer Proteins*/genetics ; Cholesterol Ester Transfer Proteins*/metabolism ; Diet, High-Fat*/adverse effects ; Metabolic Syndrome*/genetics ; Metabolic Syndrome*/metabolism ; Apolipoprotein E3*/genetics ; Apolipoprotein E3*/metabolism; Animals ; Mice ; Bile Acids and Salts/metabolism ; Cholesterol/metabolism ; Fatty Acids/metabolism ; Glucose/metabolism ; Liver/metabolism ; Longitudinal Studies ; Phenotype ; Systems Analysis ; Triglycerides
    • 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.
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    • Grant Information:
      FP7- HEALTH n°305707 European Union; 2015T068 CVON; 2009T038 CVON; FP7-603091 European Union
    • Contributed Indexing:
      Keywords: APOE3; CETP; bile acid; cholesterol; computational modeling; energy expenditure; metabolic syndrome; triglycerides
    • Accession Number:
      0 (Bile Acids and Salts)
      97C5T2UQ7J (Cholesterol)
      0 (Cholesterol Ester Transfer Proteins)
      0 (Fatty Acids)
      IY9XDZ35W2 (Glucose)
      0 (Triglycerides)
      0 (Apolipoprotein E3)
      0 (apolipoprotein E3 (Leidein))
    • Publication Date:
      Date Created: 20221126 Date Completed: 20221205 Latest Revision: 20221213
    • Publication Date:
      20250114
    • Accession Number:
      PMC9698005
    • Accession Number:
      10.3390/nu14224936
    • Accession Number:
      36432620