Abstract
Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given.
Highlights
Increased plasma cholesterol is a known risk factor for cardiovascular disease
This study presents Particle Profiler, a model framework capable of analyzing cholesterol and triglyceride data by describing how lipoprotein production, remodeling, and uptake processes depend on lipoprotein particle size
Our model implementation was able to reproduce the original model fits by Packard et al, requiring only six parameters to describe all modeled lipolysis and uptake processes
Summary
Model framework The lifecycle of lipoprotein particles consists of three processes: production, remodeling, and uptake. Mass balances can be written for each of the subclasses, and for the sum of all subclasses in any particle size range These equate what comes in from the lipolysis and direct production with what leaves through lipolysis and direct uptake. The model framework contains the new concept that rate constants of processes in different subclasses vary nonlinearly as a function of particle diameter. The parameters of these nonlinear functions can be estimated by comparing experimental data on particle concentrations and fluxes in lipoprotein size classes to the model prediction for those size classes. The size-dependent models for production, lipolysis, and uptake are based on biological hypotheses explained below These hypotheses were translated into mathematical equations to generate a first model instance. A full motivation of all equations can be found in the supplementary data
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