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 β-very low density lipoproteins (β-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-β-VLDL and β-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-β) 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-β-VLDL and β-VLDL from atypical and typical dys-β subjects were indistinguishable. However, lipoproteins from atypical and typical dys-β subjects differed in their affinity for the apo-B,E(LDL) receptor on cultured human fibroblasts. The pre-β-VLDL and β-VLDL from atypcial dys-β subjects had 640- or 17-fold higher affinity, respectively, than did corresponding lipoproteins from typical dys-β subjects. The higher binding affinity of lipoproteins from atypical dys-β 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 β-VLDL in atypical than in typical dys-β subjects in vivo, the mechanism of β-VLDL accumulation may differ in these two groups.