Preliminary model for human lipoprotein metabolism in hyperlipoproteinemia

A model is proposed for the metabolism of plasma lipoprotein apoproteins based on studies of a hyperlipoproteinemic subject who received 2.5 mCi[3H]leucine intravenously. Measurements included apoprotein specific activities (apo-B and apo-C) of very low density lipoprotein (VLDL) and of three low density lipoprotein (LDL) subspecies, Sf 17 LDL, Sf 10 LDL, and Sf 4 LDL. Activities of plasma albumin were also determined. The data were analyzed using a compartmental model and the SAAM computer program. A chain-like series of compartments were necessary to simulate plasma VLDL kinetics, suggesting a multistep delipidation process. The data are consistent with the notion that VLDL is the dominant LDL precursor. Two modes of conversion from VLDL to LDL are required. After partial delipidation some VLDL is converted to the Sf 17 LDL, while the remainder undergoes further delipidation before being converted to Sf 4 LDL, the major plasma LDL component. Some direct release of LDL into plasma had to be introduced to fit the data, about 24% of total LDL production. The three LDL subspecies follow a precursor-product relationship (Sf 17 leads to Sf 10 leads to Sf 4). The analysis also indicates that in using labeled leucine as a tracer, the slow exchange of leucine with the total body protein pool must be considered in trying to resolve the LDL subsystem and in the estimation of steady-state apoprotein levels. In view of the fact that the proposed model is based predominantly on the data from a single patient, no generalizations can be made about parameter values. The study is most valuable, however, in pointing out metabolic pathways not considered before and in calling attention to variables that must be considered in the design of experiments to study lipoprotein kinetics.