Hepatic lipoprotein metabolism

A problem presented at the UK MMSG Oxford 2005.

Presented by:
Dr Kim Jackson (School of Food Biosciences, The University of Reading)
Dr Brendan O'Malley (Corporate Research Biosciences, Unilever)
Dr Laura Pickersgill (Corporate Research Biosciences , Unilever)
Prof Christine Williams (School of Food Biosciences, University of Reading)
H Byrne, K Jackson, B O'Malley, J Panovska, L Pickersgill, M Tindall, J Wattis, C Williams

Problem Description

Diets rich in saturated fatty acids have been shown to elevate the level of plasma Low density Lipoprotein cholesterol (LDL-C), a major risk factor for the development of Coronary Heart Disease (CHD). The level of circulating LDL-C is influenced by both the rate of production and the rate of removal of LDL from the plasma compartment. The major route of LDL removal from the circulation is via LDL receptor (LDLR)-mediated endocytosis in the liver.

Apolipoprotein (apo) E containing triglyceride-rich lipoproteins (TRL) can also bind to the LDLR. Following a fat-containing meal, the levels of TRL increase in the circulation and elevations in the magnitude and length of this response have been associated with different dietary fats and to the development of raised LDL-C. Studies have shown that the type of dietary fat determines the fatty acid and apo E composition of TRL, and that this in turn influences their uptake by the liver. Evidence is accruing to suggest that fatty-acid-induced changes in the composition of TRL particles determines their affinity for the LDLR leading to differential competition with LDL for uptake by the liver, and hence influencing plasma LDL-C levels.

Using data from in-vitro experiments in which hepatic LDL uptake is measured in the presence of TRL isolated from individuals following different meals, the MMSG will explore two hypotheses as to the mechanism by which TRL of differing composition affect LDL uptake.

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Study Group Report

Two mathematical models of lipoprotein particle metabolism by liver cells (hepatocytes) are formulated. The first model describes low density lipoprotein (LDL) particle uptake using a discrete model formulation and allows differences in the number of free, bound and internalised LDL particles to be elucidated. A second continuum model provides a description of LDL and very low density lipoprotein (VLDL) particle uptake and the competition between the particles for free LDL receptors. Both models provide initial insight into testing biological hypotheses on the competition between LDL and VLDL particle binding and uptake. Comparison with experimental data is made where appropriate and suggestions for further model development are made.

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