Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.2.7 (heparinase)
 1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia. 817 73

In this study, we investigated the impact of the common apoE polymorphism on apoE metabolism and cholesterol homeostasis in monocyte-derived macrophages isolated from E2/2, E3/3, and E4/4 subjects. Unloaded cells of all genotypes contained similar amounts of free cholesterol, cholesteryl ester, and apoE mRNA. E3/3 cells secreted 77 and 30% more apoE than E2/2 or E4/4 cells, respectively. Pulse-chase studies confirmed that the apoE secretion rate was greatest in E3/3 and least in E2/2 cells and showed that a portion of apoE2, but not apoE3 or apoE4, was degraded intracellularly. Surface binding of apoE was greatest in E4/4 cells, as revealed by heparinase treatment. On cholesterol loading with acetylated LDL, apoE mRNA levels and protein secretion rose most in E4/4 and least in E2/2 cells. Cholesterol and cholesteryl ester content, however, rose most in E2/2 and least in E3/3 cells. Incubations with 3H-cholesterol-labeled acetylated LDL revealed that E2/2 cells were most efficient at secreting cholesterol. The greatest reuptake of 3H-cholesterol-rich particles was from E4/4 macrophage- conditioned media. Thus, E2/2 macrophages, despite a low apoE secretion rate, are protected from cholesterol storage by apoE-mediated cholesterol efflux. In E3/3 macrophages, cholesterol accumulation is lessened by a high basal apoE secretion rate. E4/4 macrophages secrete the most apoE but lack effective net cholesterol efflux due to enhanced surface binding and reuptake of cholesterol-rich particles.
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PMID:Phenotype-dependent differences in apolipoprotein E metabolism and in cholesterol homeostasis in human monocyte-derived macrophages. 954 97