A computational framework to analyze plasma lipoprotein metabolism in mice

F.L.P. Sips, C.A. Tiemann, C.W. Hilbers, N.A.W. Riel, van

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Question The characteristics of plasma lipoprotein profiles codetermine metabolic and cardiovascular disease risks. One example concerns the distribution of particle sizes, which provides information to assess the risk of atherosclerotic plaque formation. The factors involved in the generation of pro-atherogenic lipoprotein particles are not fully understood. We developed a computational framework to investigate the molecular mechanisms that underlie the characteristics of plasma lipoprotein distributions in mice. Methods Multiple data sets of wild-type C57BL/6J mice were acquired1 and included in the computational analysis. These sets contained distributions of plasma triglyceride and cholesterol concentrations obtained via fast protein liquid chromatography (FPLC), as well as information about the production of very low density lipoprotein (VLDL) particles. A computational model consisting of ordinary differential equations and describing the production and remodeling as well as uptake of endogenous ApoB and ApoA containing lipoproteins was constructed. The different lipoprotein classes are described by defining grids containing particles of varying cholesterol and triglyceride content. A calibration function was determined to relate FPLC fraction to the lipoprotein concentrations in the computational framework. Results A computational model simultaneously describing VLDL and high density lipoprotein (HDL) metabolism was constructed, in which the included particle types can assume different compositions and sizes. Results from the computational analysis indicated that experimentally observed profiles of triglyceride and cholesterol in the VLDL and HDL fractions can be reproduced by the model. Furthermore, the model provided predictions of the compositional contributions of free cholesterol, cholesterylester, and phospholipids. The prediction of latter unmeasured components was accomplished by defining additional calibration functions based on compositional data of different lipoprotein types. Conclusion A computational framework was presented to investigate plasma lipoprotein metabolism in mice. The framework provides opportunities to investigate a variety of phenotypes in which lipoprotein metabolism is disturbed resulting in changes in particle composition and size. The time-dependent changes in plasma lipoprotein metabolism upon administration of T0901317, a potential pharmaceutical compound for anti-atherosclerotic therapies, are of particular interest. 1. Grefhorst A., M. H. Oosterveer, G. Brufau, M. Boesjes, F. Kuipers, A. K. Groen, Pharmacological LXR activation reduces presence of SR-B1 in liver membranes contributing to LXR-mediated induction of HDL-cholesterol, Atherosclerosis, Available online 3 March 2012
Original languageEnglish
Title of host publicationAbstract presented at the 4th Conference on Systems Biology of Mammalian Cells (SBMC) 2012, 9-11 July 2012, Leipzig, Germany
Publication statusPublished - 2012
Event4th Conference on Systems Biology of Mammalian Cells (SBMC 2012), July 9-11, 2012, Leipzig, Germany - Leipzig, Germany
Duration: 9 Jul 201211 Jul 2012


Conference4th Conference on Systems Biology of Mammalian Cells (SBMC 2012), July 9-11, 2012, Leipzig, Germany
Abbreviated titleSBMC 2012


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