Mathematical model for low density lipoprotein (LDL) endocytosis by hepatocytes.


Wattis, JA; O'Malley, B; Blackburn, H; Pickersgill, L; Panovska, J; Byrne, HM; Jackson, KG; (2008) Mathematical model for low density lipoprotein (LDL) endocytosis by hepatocytes. Bulletin of mathematical biology, 70 (8). pp. 2303-33. ISSN 0092-8240 DOI: https://doi.org/10.1007/s11538-008-9347-9

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Abstract

Individuals with elevated levels of plasma low density lipoprotein (LDL) cholesterol (LDL-C) are considered to be at risk of developing coronary heart disease. LDL particles are removed from the blood by a process known as receptor-mediated endocytosis, which occurs mainly in the liver. A series of classical experiments delineated the major steps in the endocytotic process; apolipoprotein B-100 present on LDL particles binds to a specific receptor (LDL receptor, LDL-R) in specialized areas of the cell surface called clathrin-coated pits. The pit comprising the LDL-LDL-R complex is internalized forming a cytoplasmic endosome. Fusion of the endosome with a lysosome leads to degradation of the LDL into its constituent parts (that is, cholesterol, fatty acids, and amino acids), which are released for reuse by the cell, or are excreted. In this paper, we formulate a mathematical model of LDL endocytosis, consisting of a system of ordinary differential equations. We validate our model against existing in vitro experimental data, and we use it to explore differences in system behavior when a single bolus of extracellular LDL is supplied to cells, compared to when a continuous supply of LDL particles is available. Whereas the former situation is common to in vitro experimental systems, the latter better reflects the in vivo situation. We use asymptotic analysis and numerical simulations to study the longtime behavior of model solutions. The implications of model-derived insights for experimental design are discussed.

Item Type: Article
Faculty and Department: Faculty of Public Health and Policy > Dept of Global Health and Development
PubMed ID: 18716843
Web of Science ID: 259962900009
URI: http://researchonline.lshtm.ac.uk/id/eprint/2097775

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