Title
A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans
Author
van de Pas, N.C.A.
Woutersen, R.A.
van Ommen, B.
Rietjens, I.M.C.M.
de Graaf, A.A.
Publication year
2012
Abstract
Increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. This study describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. This model was directly adapted from a PBK model for mice by incorporation of the reaction catalyzed by cholesterol ester transfer protein and contained 21 biochemical reactions and eight different cholesterol pools. The model was calibrated using published data for humans and validated by comparing model predictions on plasma cholesterol levels of subjects with 10 different genetic mutations (including familial hypercholesterolemia and Smith-Lemli-Opitz syndrome) with experimental data. Average model predictions on total cholesterol were accurate within 36% of the experimental data, which was within the experimental margin. Sensitivity analysis of the model indicated that the HDL cholesterol (HDL-C) concentration was mainly dependent on hepatic transport of cholesterol to HDL, cholesterol ester transfer from HDL to non-HDL, and hepatic uptake of cholesterol from non-HDL-C. Thus, the presented PBK model is a valid tool to predict the effect of genetic mutations on cholesterol concentrations, opening the way for future studies on the effect of different drugs on cholesterol levels in various subpopulations in silico. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
Subject
EELS - Earth, Environmental and Life Sciences
Life
Healthy Living
Food and Nutrition
HDL cholesterol
LDL cholesterol
Mutations
PBK modeling
Plasma cholesterol
QS - Quality & Safety
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DOI
https://doi.org/10.1194/jlr.m031930
TNO identifier
466427
ISSN
0022-2275
Source
Journal of Lipid Research, 53 (53), 2734-2746
Document type
article