A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man. Niek C.A.

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1 A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man Niek C.A. van de Pas

2 A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man Niek C.A. van de Pas

3 Thesis committee Thesis supervisors Prof. Dr. Ir. I.M.C.M. Rietjens Professor of Toxicology Wageningen University Prof. Dr. R.A. Woutersen Senior Scientist; Toxicologic Pathologist TNO, Zeist & Professor of Toxicology Wageningen University Thesis co-supervisor Dr. ir. A.A. de Graaf Senior Scientist Fluxomics TNO, Zeist Other members Prof. dr. M.R. Müller, Wageningen University Prof. dr. L.M. Havekes, Leiden University Medical Center Prof. dr. A.K. Groen, University of Groningen Dr. A. P. Freidig, AMT Biopharma, Amsterdam This research was conducted under the auspices of the graduate school VLAG

4 A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man Niek C.A. van de Pas Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. dr. M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 23 December 2011 at 4 pm in the Aula

5 Niek C.A. van de Pas A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man Thesis, Wageningen University, Wageningen, NL (2011) with with summary in Dutch ISBN:

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8 Table of contents Chapter 1. General introduction 9 Chapter 2. Systematic construction of a conceptual minimal model of plasma cholesterol levels based on knockout mouse phenotypes 29 Chapter 3. A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse 57 Chapter 4. A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans 87 Chapter 5. Predicting individual responses to pravastatin using a kinetic model for plasma cholesterol concentrations 115 Chapter 6. Predicting individual response to CETP inhibitors using a kinetic model for cholesterol concentrations 141 Chapter 7. Summary, general discussion, and future prespectives 159 Abbreviations 181 Nederlandse samenvatting 183 List of publications 191 Dankwoord 193 Curriculum Vitae 195 List of publications 197 Overview of completed training activities 200

9 Curriculum Vitae Curriculum Vitae Nicolaas Catharina Antonius (Niek) van de Pas was born on 17 th October 1982 in Goes. He grew up in Kloetinge and from 1995 he attended Het Goese Lyceum in Goes, where he completed his VWO in Then he moved to Leiden to study Life Science & Technology at Leiden University and Delft University of Technology. In 2004 he obtained his BSc. degree cum laude with a thesis entitled: Molecular modeling of the antitumor drug Bleomyin under supervision of dr. F. Buda and dr. A. Karawajczyk. In 2007 he obtained his MSc. degree cum laude with a thesis entitled: Mathematical modeling of the TOR signal transduction pathway under supervision of Prof. dr. ir. J.J. Heijnen and dr. E. Nikerel. From September 2007 to August 2011 Niek worked as a PhD student at the Section Toxicology of Wageningen University and the Netherlands Organization for Applied Scientific Research (TNO) on mathematical modeling of plasma cholesterol levels which resulted in this thesis. During this project, Niek completed the educational programme of the Graduate School VLAG. Between September 2011 and December 2011, Niek worked as a junior researcher at Wageningen University and TNO. From January 2012, he will work as a software engineer at the NCIM-group. 195

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11 List of publications

12 Publications List of Publications De Graaf, A.A. Biochim Biophys Acta (5): , (2011) A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse. Van de Pas, N.C.A.; Soffers, A.E.M.F.; Freidig, A.P.; Van Ommen, B.; Woutersen, R.A.; Rietjens, I.M.C.M.; and De Graaf A.A. Biochim Biophys Acta (6):646-54, (2010). Systematic construction of a conceptual minimal model of plasma cholesterol levels based on knockout mouse phenotypes. Van Schalkwijk, D.B.; De Graaf, A.A.; Van Ommen, B.; Van Bochove, K.; Rensen, P.C.; Havekes, L.M.; Van de Pas, N.C.A.; Hoefsloot, H.C.; Van der Greef, J.; and Freidig, A.P.; J Lipid Res. 50 (12): (2009) Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size. De Graaf, A.A. (submitted) A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in humans. De Graaf, A.A. (submitted). Predicting individual responses to pravastatin using a kinetic model for plasma cholesterol concentrations. De Graaf, A.A. (in preparation). Predicting individual response to CETP inhibitors using a kinetic model for cholesterol concentrations. Abstracts 198 De Graaf, A.A. A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man. [Oral presentation: Symposium at Nestlé Research center, 2011, Lausanne, Switzerland]. De Graaf, A.A. Analyzing the personalized response to pravastatin using a PBK model of cholesterol metabolism. [Oral presentation: at the NVT Annual Meeting, 2011, Zeist, The Netherlands].

13 Publications De Graaf, A.A. Systems biology model of cholesterol homeostasis. [Oral presentation: at the ETSB symposium, Utrecht, The Netherlands]. De Graaf, A.A. Computer modeling of dyslipidemia: analyzing factors that affect plasma cholesterol levels, [Accepted for the 4th International Congress on Prediabetes and the Metabolic Syndrome, 2011, Madrid, Spain]. Van de Pas, N.C.A.; Rietjens, I.M.C.M.; Woutersen, R.A.; and De Graaf, A.A. A model for the prediction of cholesterol plasma levels based on the enterohepatic circulation. [Published in VLAG Current Research 2010]. De Graaf, A.A. A physiologically-based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in the mouse. [Accepted for European Lipoprotein Club, 2010, Tutzing, Germany]. De Graaf, A.A.; Van de Pas, N.C.A; Soffers, A.E.M.F.; Woutersen, R.A.; Van Ommen, B.; and Rietjens, I.M.C.M. A systematically constructed conceptual model of cholesterol metabolism. [Accepted for Experimental Biology 2010 Anaheim, CA, USA]. De Graaf, A.A. A physiologically-based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in the mouse. [Accepted for NVT Annual Meeting, 2010, Zeist, The Netherlands]. Van de Pas, N.C.A.; Soffers, A.E.M.F.; Freidig, A.P.; Van Ommen, B.; Woutersen R.A.; Rietjens, I.M.C.M.; and De Graaf A.A. A systematically constructed conceptual model of cholesterol metabolism. [Accepted for NVT Annual Meeting, 2009, Veldhoven, The Netherlands]. Van de Pas, N.C.A.; Soffers, A.E.M.F.; Freidig, A.P.; Van Ommen, B.; Woutersen R.A.; Rietjens, I.M.C.M.; and De Graaf A.A. A conceptual model of cholesterol metabolism constructed using the phenotypes of knockout mouse models. [Accepted for Gordon Research Conference: Molecular & Cellular Biology Of Lipids, 2009, Waterville Valley, NH, USA]. Van de Pas, N.C.A.; Soffers, A.E.M.F.; Freidig, A.P.; Van Ommen, B.; Woutersen R.A.; Rietjens, I.M.C.M.; and De Graaf A.A. A systematic inventory and analysis of mouse knock out models in cholesterol metabolism. [Accepted for Nutrigenomics Organisation (NuGO) week, 2008, Potsdam, Germany]. 199

14 Training activities Overview of completed training activities Completed courses and attended meetings include: 200 Systems Biology modelling workshop (NuGO) 2007 VLAG PhD week 2008 PBPK Modeling and Risk Assessment (The Hamner) 2008 Atherosclerosis (LACDR) 2008 Congress: NuGO week (NuGO) 2008 IP workshop (TNO) 2008 Spider introduction course (Broekhuis) 2008 VLAG PhD week (VLAG) 2008 Parameter estimation and structure identification (WUR) 2008 Workshop Gezonde Voeding 2009 (TNO) 2009 NVT jaarvergadering (NVT) 2009 Experimental design in systems biology (Lorentz Institute) 2009 Systems biology day (Biometris) 2009 Molecular & Cellular Biology Of Lipids (Gordon) 2009 Symposium Bibliometrics (WUR) 2009 NWO talent class (NWO) 2010 Interpersonal Communication for PhD students (WUR) 2010 Pharma workshop (TNO) 2010 MATLAB Advanced programming course (Mathworks) 2010 NVT jaarvergadering 2010 (including PhD day) (NVT) 2010 Congress: 32 nd European Lipoprotein Club meeting (ELC) 2010 NVT jaarvergadering 2010 (including PhD day) (TNO) 2011 Systems biology symposium (TNO) 2011 Scientific writing (WUR) 2011 Career perspectives (VLAG) 2011 Toxicology PhD trip 2011 Approved by Graduate School VLAG Financial support from Wageningen University for printing this thesis is gratefully acknowledged.

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