A continuum receptor model of hepatic lipoprotein metabolism.
A mathematical model describing the uptake of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles by a single hepatocyte cell is formulated and solved. The model includes a description of the dynamic change in receptor density on the surface of the cell due to the binding and dissociation of the lipoprotein particles, the subsequent internalisation of bound particles, receptors and unbound receptors, the recycling of receptors to the cell surface, cholesterol dependent de novo receptor formation by the cell and the effect that particle uptake has on the cell's overall cholesterol content. The effect that blocking access to LDL receptors by VLDL, or internalisation of VLDL particles containing different amounts of apolipoprotein E (we will refer to these particles as VLDL-2 and VLDL-3) has on LDL uptake is explored. By comparison with experimental data we find that measures of cell cholesterol content are important in differentiating between the mechanisms by which VLDL is thought to inhibit LDL uptake. We extend our work to show that in the presence of both types of VLDL particle (VLDL-2 and VLDL-3), measuring relative LDL uptake does not allow differentiation between the results of blocking and internalisation of each VLDL particle to be made. Instead by considering the intracellular cholesterol content it is found that internalisation of VLDL-2 and VLDL-3 leads to the highest intracellular cholesterol concentration. A sensitivity analysis of the model reveals that binding, unbinding and internalisation rates, the fraction of receptors recycled and the rate at which the cholesterol dependent free receptors are created by the cell have important implications for the overall uptake dynamics of either VLDL or LDL particles and subsequent intracellular cholesterol concentration.
Tindall
M J
MJ
Centre for Mathematical Biology, Mathematical Institute, 24-29 St Giles', Oxford OX1 3LB, UK. m.tindall@reading.ac.uk
Wattis
J A D
JA
O'Malley
B J
BJ
Pickersgill
L
L
Jackson
K G
KG
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001667:Binding, Competitive; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008954:Models, Biological; D011973:Receptors, LDL / Q000378:metabolism*
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D002784:Cholesterol