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Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size

Author: Schalkwijk, D.B. van · Graaf, A.A. de · Ommen, B. van · Bochove, K. van · Rensen, P.C.N. · Havekes, L.M. · Pas, N.C.A. van de · Hoefsloot, H.C.J. · Greef, J. van der · Freidig, A.P.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 12, 50, 2398-2411
Identifier: 271331
doi: doi:10.1194/jlr.M800354-JLR200
Keywords: Health · Physiological Sciences · Data analysis · Genetic polymorphism · Hepatic lipase · Kinetics · Lipoprotein lipase · Mathematical modeling · Stable isotope flux data

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 profi le data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given. © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.