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Mathematical modelling of LDL and VLDL endocytosis by HepG2 cells.
by
Jonathan Wattis
University of Nottingham
Coauthors: Brendan O'Malley (Unilever Corporate Research, UK),
Marcus Tindall (University of Oxford, UK),
Laura Pickersgill (Unilever Corporate Research, UK),
Hannah Blackburn (Unilever Corporate Research, UK),
Helen Byrne (University of Nottingham, UK),
Kim Jackson (University of Reading, UK),
Jasmina Panovska (Unilever Corporate Research, UK).
Individuals with elevated levels of low-density-lipoprotein cholesterol (LDL-C) in their plasma are considered to at risk of developing coronary heart disease. LDL particles are removed from the body mainly by hepatocytes through receptor-mediated endocytosis. Apolipoprotein B-100 present on the surface of LDL particles binds to receptors in pits on the surface of hepatocytes. Upon internalisation of a pit, the bound complex of LDL and receptor is degraded into its constituent parts (cholesterol, fatty acids and amino acids), which are released for use by the cell or are excreted. Very low-density lipoprotein particles (VLDL) are known to inhibit the take-up of LDL [Jackson et al J Lipid Res 47, 393, (2006)].
We formulate a mathematical model of the binding, internalisation and processing of LDL and VLDL particles by cells. The model is calibrated to experimental data of Brown & Goldstein [PNAS 76, 3330, (1979)], and Harwood & Pellarin [Biochem J 323, 649, (1997)]. We find good agreement with in vitro data on LDL-take up, and inhibition of take-up by VLDL. As well as the 'single bolus' scenario where a large dose of lipoprotein is delivered at the start of the experiment, we consider the more realistic (in vivo) case where lipoprotein is continually delivered to the system. We show how the the average occupancy of pits, and the proportions of receptors which are free, bound, or internalised changes over time. We analyse how the cell's flexibility in adapting to changes in its environment depends on the efficiency of receptor-recycling, how different types of VLDL influence LDL takeup, and differences in behaviour exhibited by the single-bolus and continual-delivery models.
Date received: April 7, 2008
Copyright © 2008 by the author(s). The author(s) of this document and the organizers of the conference have granted their consent to include this abstract in Atlas Conferences Inc. Document # cawd-21.