A mathematical model of fatty acid metabolism and VLDL assembly in human liver

Abstract

The lipid composition of very-low-density lipoprotein (VLDL) in plasma is crucial for human health. A pre-requisite for the alteration of VLDL composition is a co-ordinated understanding of the complex interactions in VLDL assembly. In order to determine the potential effects of changes in substrate availability on VLDL lipid composition, we constructed, parameterized and evaluated a mechanistic mathematical model of the biosynthesis of triglycerides, phospholipids, and cholesterol esters and the assembly of VLDL in human hepatocytes. Using published data on human liver metabolism, the model was also used to provide insight into the complex process of lipid metabolism and to estimate the affinities of different liver enzymes for different fatty acids (FA). For example, we found that Δ6-desaturase is 19 times more selective for C18:3n-3 than C18:2n-6, stearoyl-CoA-desaturase is 2.7 times more selective for C18:0 than C16:0, Δ5-desaturase desaturates C20:4n-3 preferentially over C20:3n-6 and FA elongase preferentially elongates C18:3n-6. The model was also used to predict the plasma free fatty acid (FFA) composition required to generate a prescribed change in plasma lipoprotein FA composition. Furthermore, the model was tested against a published human feeding trial that investigated the effect of changes in dietary FA composition on human plasma lipid FA composition. The model is a useful tool for predicting the effect of changes in plasma FFA composition on plasma lipoprotein lipid FA composition.