Heparan sulfate proteoglycans mediate internalization and degradation of beta-VLDL and promote cholesterol accumulation by pigeon macrophages.
Pigeon and rabbit beta-migrating very low density lipoprotein (beta-VLDL) are similar in size and composition, yet rabbit beta-VLDL consistently stimulates greater cholesteryl ester accumulation in pigeon peritoneal macrophages than does pigeon beta-VLDL. The purpose of this study was to determine the mechanism of this difference. Pigeon beta-VLDL bound to both a high and low affinity site while rabbit beta-VLDL bound primarily to a low affinity site. The high affinity site had the characteristics of the LDL receptor. Most rabbit beta-VLDL and some pigeon beta-VLDL bound to the low affinity site that was not down-regulated by cholesterol loading. beta-VLDL binding to the low affinity site and subsequent internalization and degradation were mediated by cell surface heparan sulfate proteoglycans (HSPG). Evidence for this includes inhibition of binding and uptake by chlorate, which prevents sulfation of proteoglycans, and by treatment with heparinase but not chondroitinase ABC. beta-VLDL uptake was stimulated by lipoprotein lipase (LpL) and apolipoprotein E (apoE), both known to bind HSPGs. Uptake and degradation of beta-VLDL were not mediated by the LDL receptor or the alpha(2)MR/LRP. Thus, binding of beta-VLDL to low affinity, high capacity HSPG binding sites on pigeon macrophages appears to directly promote internalization and degradation and is largely responsible for the greater ability of rabbit beta-VLDL to stimulate cholesterol accumulation.
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Department of Pathology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157-1072, USA.
St Clair
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D000818:Animals; D001057:Apolipoproteins E / Q000494:pharmacology; D001667:Binding, Competitive; D002478:Cells, Cultured; D002704:Chlorates / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism*; D002808:Chondroitin Lyases / Q000378:metabolism; D010856:Columbidae; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000737:chemistry; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009994:Osmolar Concentration; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D011817:Rabbits; D013696:Temperature; D013997:Time Factors
D001057:Apolipoproteins E; D002704:Chlorates; D002784:Cholesterol; D002808:Chondroitin Lyases; D004492:Edetic Acid; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate; D007457:Iodine Radioisotopes; D008071:Lipoprotein Lipase; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; C032706:sodium chlorate