Transport of Fatty Acid Molecules by Lipoprotein Micelles in the Human Body By: Minxue Jia A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Master of Science in Engineering Baltimore, Maryland May, 2018 Abstract Though the death rate from coronary heart disease (CHD) has declined over the last several decades, CHD still remains one of the leading causes of death in the United States. Multiple lines of evidence have confirmed that Apo B-containing lipoproteins are involved in the development of atherosclerosis. The function of Apo B-containing lipoproteins is to transfer fatty acids and other lipids to peripheral organs. Two computational and mathematical methods, a deterministic ODE model and the stochastic Gillespie algorithm, are applied to model the complex lipoprotein transport and lipid metabolism of the human body for a better understanding of human’s lipid transfer system and its relationship to atherosclerosis. The ODE model is a set of differential equations which tracks the lipoproteins with an assumption of one-step transition between lipoprotein groups. While the Gillespie algorithm simulates the possible states for each lipoprotein at each step, which enables subtle track of lipoprotein transition. The two modeling methods provide a way to look at fatty acid transport qualitatively and quantitatively. The goal of this research is to obtain insight into fatty acid transport in the human body and develop strategies to prevent and treat atherosclerosis. Thesis Committee: Marc D. Donohue, Professor of Chemical Engineering Michael J. Betenbaugh, Professor of Chemical Engineering ii Table of Contents Abstract................................................................................................................................ ii Acknowledgements .............................................................................................................. iv List of Figure ........................................................................................................................ v List of Table ........................................................................................................................ vi Chapter 1. Introduction ....................................................................................................... 1 1.1 Atherosclerosis ...................................................................................................................2 1.2 Apo B Lipoproteins ............................................................................................................3 1.3 HDL & Reverse Cholesterol Transfer ................................................................................9 1.4 Lipase .............................................................................................................................. 10 1.5 CETP & PLTP ................................................................................................................. 11 1.6 Small dense LDL .............................................................................................................. 12 Modeling and Results ......................................................................................................... 14 Chapter 2. Ordinary Differential Equation Model ............................................................. 14 2.1 The lipoprotein species and transition ................................................................................... 14 2.2 Organ lipids and formation of lipoprotein ............................................................................. 15 2.3 Cholesterol ester transfer protein and sdLDL ....................................................................... 15 2.4 LDL receptor & LDL receptor related protein ...................................................................... 16 2.5 Results ................................................................................................................................... 16 Chapter 3. Modified Gillespie algorithm: ........................................................................... 28 3.1 Grouped Gillespie algorithm ................................................................................................. 28 3.2 The three tracks .................................................................................................................... 29 3.3 Organ lipids and formation of lipoprotein ............................................................................. 29 3.4 Circulation: ........................................................................................................................... 30 3.5 Lipoprotein lipase .................................................................................................................. 30 3.6 Hepatic lipase ........................................................................................................................ 31 3.7 Cholesteryl ester transfer protein .......................................................................................... 31 3.8 LDL receptor ......................................................................................................................... 32 3.9 Result .................................................................................................................................... 32 3.10 Limitation ............................................................................................................................ 34 Chapter 4. Conclusion ........................................................................................................ 36 Reference ........................................................................................................................... 37 Appendix ............................................................................................................................ 44 Appendix I Parameter for ODE .................................................................................................. 44 Appendix II Differential Equation & Matlab Code for ODE....................................................... 46 Appendix III Matlab Code for Modified Gillespie algorithms ..................................................... 76 Curriculum Vitae ............................................................................................................... 91 iii Acknowledgements I would like to greatly thank Professor Donohue for being my research advisor and for all of his guidance. I learned to model and apply computational & mathematical methods to solve complex problems from Professor Donohue’s teaching and mentoring. His support has always pushed me to strive in his lab. I would also like to thank Professor Betenbaugh for being on my thesis committee. Not only did his feedback help me understand my own research better, he kept me focused on the task at hand. In addition, I would like to thank the other students Denis Routkevitch, Gabriella Russo, Victoria Laney, Junyi Rao and Tiankai Zhang, who have helped me for my research work. Lastly, I would like to thank my friends and family, especially my parents, who have supported and helped me throughout this process and deserve all of the credit. iv List of Figure FIGURE 1. APOLIPOPROTEIN TRANSFER BETWEEN LIPOPROTEINS 6 FIGURE 2. LIPOPROTEIN METABOLISM 8 FIGURE 3. CETP ACTIVITY AND LDLS & HDLS 16 FIGURE 4. CM AND CMR CONCENTRATION AT HOMEOSTASIS STATE 17 FIGURE 5. VLDL AND IDL CONCENTRATION AT HOMEOSTASIS STATE 18 FIGURE 6. LDL CONCENTRATION AT HOMEOSTASIS STATE 18 FIGURE 7. HDL CONCENTRATION AT HOMEOSTASIS STATE 19 FIGURE 8. LIPID CONCENTRATION AND CHOLESTEROL CONTENT IN VLDL AT HOMEOSTASIS STATE 19 FIGURE 9. CM AND CMR CONCENTRATION AFTER INCREASED DIETARY LIPID INTAKE 20 FIGURE 10. VLDL & IDL CONCENTRATION AFTER INCREASED DIETARY LIPID INTAKE 21 FIGURE 11. LDL CONCENTRATION AFTER INCREASED DIETARY LIPID INTAKE 22 FIGURE 12. HDL CONCENTRATION AFTER INCREASED DIETARY LIPID INTAKE 22 FIGURE 13. HEPATIC TRIGLYCERIDE & CHOLESTEROL AFTER INCREASED DIETARY LIPID INTAKE 23 FIGURE 14. LIPID CONCENTRATION AND CHOLESTEROL CONTENT IN VLDL AFTER INCREASED DIETARY LIPID INTAKE 24 FIGURE 15. VLDL & IDL CONCENTRATION WHEN VLDL GENERATION IS LIMITED 25 FIGURE 16.LDL CONCENTRATION WHEN VLDL GENERATION IS LIMITED 25 FIGURE 17. HDL CONCENTRATION WHEN VLDL GENERATION IS LIMITED 26 FIGURE 18. LIPIDS CONCENTRATION AND AVERAGE CHOLESTEROL CONTENT IN VLDL WHEN VLDL GENERATION IS LIMITED 27 FIGURE 19. COMPOSITION OF EACH TYPE OF LIPOPROTEIN 33 FIGURE 20. BODY CONCENTRATION THROUGH TIME 33 FIGURE 21. ORGAN COMPOSITION. 34 v List of Table TABLE 1. LIPOPROTEIN SIZE, DENSITY, CONCENTRATION, COMPOSITION AND APOLIPOPROTEI 4 TABLE 2. VOLUME AND BLOOD FLOW RATE OF ORGANS 44 TABLE 3. COMPOSITION OF LIPOPROTEINS IN MOLE 44 TABLE 4. TRIGLYCERIDE CONCENTRATION OF ORGANS 44 TABLE 5. CHOLESTEROL CONCENTRATION OF ORGANS 45 TABLE 6. FATTY ACID PROFILE AND TRIGLYCERIDE MOLAR MASS 45 vi Chapter 1. Introduction The death rate from coronary heart disease (CHD) has declined noticeably recently, but CHD remains one of the leading causes of death in the United States. 1 The CHD is a disease in which a waxy substance called plaque builds up inside the coronary arteries. Coronary arteries are the heart’s network of blood vessels, and they supply oxygen-rich blood to the body. The lack of oxygen-rich blood to portions of the heart muscle leads to ischemia of myocardial tissues and consequent alteration of heart function. 2 Atherosclerosis