heparitin-sulfate and Hyperlipoproteinemias

The data described in this chapter demonstrate that the metabolic control of processes responsible for the formation, uptake and clearance of remnant particles is considerably more complex than previously believed. It now appears that several interacting reactions are involved in the process, and evidence is accumulating that defects in any one of these reactions may severely affect the optimal metabolic cascade. Proper exposure of receptor-binding domains in apoE and perhaps apoB-100 molecules is mandatory. Lipoprotein lipase-induced triglyceride hydrolysis is essential and responsible for the formation of remnant particles from secreted triglyceride-rich lipoproteins. The existence of apoE molecules that exhibit normal function is important but perhaps not always essential. Sequestration in the liver through lipoprotein lipase and/or apoE-mediated binding to heparan sulphate ('bridging' effect) appears to play an exceedingly important role during the early phase of the remnant clearance process. The 'bridging' is responsible not only for sequestration in the liver but also for enhanced uptake and lysosomal degradation of the particles. At this stage, association with the remnants of newly secreted, liver-derived apoE molecules may occur and add to the affinity of the particles towards receptors, especially if the new apoE molecules are inserted in a favourable conformational configuration. A role for the hepatic lipase has been suggested but is yet to be proved. Finally, it should be emphasized that remnants are cleared from the plasma predominantly, if not exclusively, following interaction with cellular receptors. Although the LDL receptor avidly internalizes remnant particles and is apparently active in species with a low LDL concentration (e.g. mice and rats), a second specialized and specific receptor or receptors must exist. Whether the LRP is the only remnant receptor or other, as yet unidentified, receptor proteins are also present, remains to be established. Data published in the last few years have begun to elucidate the interactions and consequences of the many reactions and proteins that are involved with the metabolism of remnant lipoproteins. More is to be learned, including the association of remnants in processes that lead to initiation/progression of atherosclerosis.

Topics: Animals; Heparitin Sulfate; Humans; Hyperlipoproteinemias; Lipoproteins; Peptide Fragments; Receptors, Cell Surface

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-->C

Topics: Animals; Apolipoproteins E; Cholesterol Esters; Fibroblasts; Heparan Sulfate Proteoglycans; Heparin Lyase; Heparitin Sulfate; Humans; Hyperlipoproteinemias; Ligands; Lipoproteins, VLDL; Liver; Polysaccharide-Lyases; Protein Binding; Proteoglycans; Rabbits; Rats; Receptors, LDL; Tumor Cells, Cultured