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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans
Niek C A van de Pas1, Ruud A Woutersen, Ben van Ommen
1The Netherlands Organization for Applied Scientific Research, 3700 AJ Zeist, The Netherlands.
Journal of Lipid Research
|October 2, 2012
Summary
A new physiologically based kinetic (PBK) model predicts human plasma cholesterol levels. This validated model accurately forecasts cholesterol changes due to genetic mutations, aiding future drug development.
Area of Science:
- Biomedical modeling
- Cardiovascular disease research
- Pharmacokinetics
Background:
- Elevated plasma cholesterol concentrations are a significant risk factor for cardiovascular disease.
- Accurate prediction of cholesterol levels is crucial for understanding disease mechanisms and developing treatments.
- Physiologically based kinetic (PBK) models offer a mechanistic approach to predicting substance concentrations in the body.
Purpose of the Study:
- To develop and validate a human physiologically based kinetic (PBK) model for predicting plasma cholesterol concentrations.
- To assess the model's accuracy in predicting cholesterol levels in individuals with various genetic mutations affecting lipid metabolism.
- To identify key factors influencing high-density lipoprotein cholesterol (HDL-C) concentrations through sensitivity analysis.
Main Methods:
- Adapted a mouse PBK model by incorporating the cholesterol ester transfer protein reaction.
- Included 21 biochemical reactions and eight distinct cholesterol pools.
- Calibrated the model with published human data and validated it against experimental data from subjects with 10 different genetic mutations.
Main Results:
- The PBK model demonstrated an average accuracy of within 36% for total cholesterol predictions compared to experimental data, falling within the experimental margin of error.
- Model predictions closely matched experimental data for individuals with genetic mutations, including familial hypercholesterolemia and Smith-Lemli-Opitz syndrome.
- Sensitivity analysis revealed that hepatic transport of cholesterol to HDL, cholesterol ester transfer, and hepatic uptake of non-HDL cholesterol are primary determinants of HDL-C.
Conclusions:
- The developed PBK model serves as a validated tool for predicting the impact of genetic mutations on human plasma cholesterol concentrations.
- This in silico approach facilitates future research into the effects of various drugs on cholesterol levels across diverse subpopulations.
- The model's predictive capability supports the advancement of personalized medicine strategies for cardiovascular disease prevention and management.
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