VARIABLE HEPARAN-SULFATE PROTEOGLYCAN BINDING OF APOLIPOPROTEIN-E VARIANTS MAY MODULATE THE EXPRESSION OF TYPE-III HYPERLIPOPROTEINEMIA

The initial step in the clearance of apolipoprotein (apo) E-enriched r emnant 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-rela ted protein or by the LDL receptor. Cholesterol-induced rabbit beta-ve ry low density lipoproteins (beta-VLDL) enriched in human apoE3 displa y 4-5-fold enhanced binding to cultured cells. The present study attem pts to determine whether recessive versus dominant type III hyperlipop roteinemia might be explained, at least in part, by a variable interac tion of the mutant forms of apoE with the HSPG and impaired uptake. Th e beta-VLDL + apoE2(Arg(158) --> Cys), which is associated with recess ive type III hyperlipoproteinemia, bound more poorly than beta-VLDL apoE3 but still possessed significant enhanced binding (similar to 2-2 .5-fold compared with beta-VLDL without added apoE) to HepG2 and McA-R H7777 cells. In comparison, beta-VLDL + apoE(Arg(142) --> Cys), beta-V LDL + apoE(Arg(145) --> Cys), and beta-VLDL + apoE-Leiden, which are a ssociated with dominant type III hyperlipoproteinemia, bound more poor ly. This same hierarchy of binding and uptake was determined by [C-14] oleate incorporation into cholesteryl esters in LDL receptor-negative cells and by secretion of apoE3 and the variant apoE forms from McA-RH 7777 cells. Furthermore, the enhanced binding of the apoE-enriched bet a-VLDL was almost totally inhibited by heparinase treatment of the cel ls, and the basal binding activity was inhibited by 80-90% following a ddition of an LDL receptor antibody capable of blocking receptor-ligan d interaction. The beta-VLDL enriched in apoE or apoE dimyristoylphosp hatidylcholine complexes bound to isolated HSPG from McA-RH7777 cells or the rat liver to a very similar degree. Likewise, the binding of be ta-VLDL plus the various forms of apoE to the LDL receptor-related pro tein on ligand blots paralleled the results of other studies. In concl usion, all of the type III hyperlipoproteinemic apoE variants are defe ctive in displaying enhanced binding to HSPG and in the cellular uptak e initiated by HSPG. However, apoE2(Arg(158) --> Cys) displayed more a ctivity than the variants associated with the dominant forms of type I II hyperlipoproteinemia. The hierarchy of binding and uptake was as fo llows: apoE3 > apoE2(Arg(158) --> Cys) > apoE(Arg(145) --> Cys) > apoE (Arg(142) --> Cys) approximate to 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 hyperlip oproteinemia and the binding and uptake of the specific apoE mutation.