title: High receptor binding affinity of lipoproteins in atypical dysbetalipoproteinemia (type III hyperlipoproteinemia).
abstract: Familial dysbetalipoproteinemia (or type III hyperlipoproteinemia) is characterized by the presence of abnormal, cholesteryl ester-rich beta-very low density lipoproteins (beta-VLDL) in the plasma. Subjects with typical dysbetalipoproteinemia are homozygous for an amino acid substitution in apolipoprotein (apo-) E at residue 158 and have defective apo-E-mediated binding of both pre-beta-VLDL and beta-VLDL to apo-B,E(LDL) (or LDL) receptors (1988. Chappell, D.A., J. Clin. Invest. 82:628-639). To understand the effect of substitutions in apo-E at sites other than residue 158, nine dysbetalipoproteinemic (dys-beta) subjects who were either homozygous or heterozygous for substitutions in apo-E at atypical sites were studied. These substitutions occurred at residue 142 (n = 6), 145 (n = 2), or 146 (n = 1) and are known to cause less defective binding than does the 158 substitution. The chemical composition and electrophoretic mobility of pre-beta-VLDL and beta-VLDL from atypical and typical dys-beta subjects were indistinguishable. However, lipoproteins from atypical and typical dys-beta subjects differed in their affinity for the apo-B,E(LDL) receptor on cultured human fibroblasts. The pre-beta-VLDL and beta-VLDL from atypical dys-beta subjects had 640- or 17-fold higher affinity, respectively, than did corresponding lipoproteins from typical dys-beta subjects. The higher binding affinity of lipoproteins from atypical dys-beta subjects was associated with a higher ratio of apo-E to total apo-C. Since higher binding affinity should cause more rapid receptor-mediated clearance of beta-VLDL in atypical than in typical dys-beta subjects in vivo, the mechanism of beta-VLDL accumulation may differ in these two groups.
authors.affiliation: Gladstone Foundation Laboratories for Cardiovascular Disease, Department of Internal Medicine, University of California, San Francisco 94140.
authors.forename: D A
authors.initials: DA
authors.lastname: Chappell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D001667:Binding, Competitive; D002478:Cells, Cultured; D002648:Child; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000302:isolation & purification; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D018110:Receptors, Lipoprotein
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C032531:apolipoprotein B,E receptor