The initial step in the clearance of apolipoprotein (apo) E-enriched remnant 
lipoproteins from the plasma appears to be sequestration within the liver 
mediated by their binding to heparan sulfate proteoglycans (HSPG). The 
surface-bound remnants are believed to be internalized by their interaction with 
the low density lipoprotein (LDL) receptor-related protein or by the LDL 
receptor. Cholesterol-induced rabbit beta-very low density lipoproteins 
(beta-VLDL) enriched in human apoE3 display 4-5-fold enhanced binding to 
cultured cells. The present study attempts to determine whether recessive versus 
dominant type III hyperlipoproteinemia might be explained, at least in part, by 
a variable interaction of the mutant forms of apoE with the HSPG and impaired 
uptake. The beta-VLDL+apoE2(Arg158-->Cys), which is associated with recessive 
type III hyperlipoproteinemia, bound more poorly than beta-VLDL+apoE3 but still 
possessed significant enhanced binding (approximately 2-2.5-fold compared with 
beta-VLDL without added apoE) to HepG2 and McA-RH7777 cells. In comparison, 
beta-VLDL+apoE(Arg142-->Cys), beta-VLDL+apoE(Arg145-->Cys), and 
beta-VLDL+apoE-Leiden, which are associated with dominant type III 
hyperlipoproteinemia, bound more poorly. This same hierarchy of binding and 
uptake was determined by [14C]oleate incorporation into cholesteryl esters in 
LDL receptor-negative cells and by secretion of apoE3 and the variant apoE forms 
from McA-RH7777 cells. Furthermore, the enhanced binding of the apoE-enriched 
beta-VLDL was almost totally inhibited by heparinase treatment of the cells, and 
the basal binding activity was inhibited by 80-90% following addition of an LDL 
receptor antibody capable of blocking receptor-ligand interaction. The beta-VLDL 
enriched in apoE or apoE-dimyristoylphosphatidylcholine complexes bound to 
isolated HSPG from McA-RH7777 cells or the rat liver to a very similar degree. 
Likewise, the binding of beta-VLDL plus the various forms of apoE to the LDL 
receptor-related protein on ligand blots paralleled the results of other 
studies. In conclusion, all of the type III hyperlipoproteinemic apoE variants 
are defective in displaying enhanced binding to HSPG and in the cellular uptake 
initiated by HSPG. However, apoE2(Arg158-->Cys) displayed more activity than the 
variants associated with the dominant forms of type III hyperlipoproteinemia. 
The hierarchy of binding and uptake was as follows: apoE3 > apoE2(Arg158-->Cys) 
> apoE(Arg145-->Cys) > apoE(Arg142-->Cys) approximately apoE-Leiden (the latter 
two usually displaying very little, if any, enhanced binding and uptake). Thus, 
a correlation exists between the mode of expression of type III 
hyperlipoproteinemia and the binding and uptake of the specific apoE mutation.