A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse.
Biochim Biophys Acta
; 1811(5): 333-42, 2011 May.
Article
em En
| MEDLINE
| ID: mdl-21320632
ABSTRACT
The LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) concentrations are determined by the activity of a complex network of reactions in several organs. Physiologically-based kinetic (PBK) computational models can be used to describe these different reactions in an integrated, quantitative manner. A PBK model to predict plasma cholesterol levels in the mouse was developed, validated, and analyzed. Kinetic parameters required for defining the model were obtained using data from published experiments. To construct the model, a set of appropriate submodels was selected from a set of 65,536 submodels differing in the kinetic expressions of the reactions. A submodel was considered appropriate if it had the ability to correctly predict an increased or decreased plasma cholesterol level for a training set of 5 knockout mouse strains. The model thus defined consisted of 8 appropriate submodels and was validated using data from an independent set of 9 knockout mouse strains. The model prediction is the average prediction of 8 appropriate submodels. Remarkably, these submodels had in common that the rate of cholesterol transport from the liver to HDL was not dependent on hepatic cholesterol concentrations. The model appeared able to accurately predict in a quantitative way the plasma cholesterol concentrations of all 14 knockout strains considered, including the frequently used Ldlr-/- and Apoe-/- mouse strains. The model presented is a useful tool to predict the effect of knocking out genes that act in important steps in cholesterol metabolism on total plasma cholesterol, HDL-C and LDL-C in the mouse.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
/
Colesterol
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2011
Tipo de documento:
Article