Pre-beta-very low density lipoproteins as precursors of beta-very low density lipoproteins. A model for the pathogenesis of familial dysbetalipoproteinemia (type III hyperlipoproteinemia).
The physical, chemical, and receptor binding properties of very low density lipoprotein (VLDL) fractions from familial dysbetalipoproteinemic (dys-beta) subjects, homozygous for apolipoprotein (apo-) E2 (E2/2 phenotype), and subjects with the E3/3 phenotype were studied to gain insights into the pathogenesis of dysbetalipoproteinemia, a disorder characterized by the presence of beta-VLDL in the plasma. Pre-beta-VLDL from dys-beta subjects were larger (27 vs. 17 x 10(6) D) and more triglyceride rich (68 vs. 43% dry weight) than beta-VLDL. Pre-beta-VLDL predominated in the Sf greater than 100 flotation fraction, whereas beta-VLDL predominated in the Sf 20-60 fraction. Because lipolysis converts large VLDL (Sf greater than 100) in vivo to smaller, more cholesteryl ester-rich VLDL (Sf 20-60), it is likely that pre-beta-VLDL are precursors of beta-VLDL. Although beta-VLDL were not found in type V hyperlipidemic E3/3 subjects, they were induced by intravenous heparinization, suggesting that lipolysis of pre-beta-VLDL in vivo can result in beta-VLDL formation. Similarly, heparinization of a dys-beta subject produced more beta-VLDL, at the expense of pre-beta-VLDL. The pre-beta-VLDL from normolipidemic and type V hyperlipidemic E3/3 subjects, respectively, had 90 and 280 times the affinity for the apo-B,E(LDL) receptor than did the pre-beta-VLDL from dys-beta subjects. Heparin-induced beta-VLDL from type V hyperlipidemic subjects had a sixfold higher binding affinity than did heparin-induced beta-VLDL from dys-beta subjects. These data suggest that pre-beta-VLDL from E2/2 subjects interact poorly with lipoprotein receptors in vivo, decreasing their receptor-mediated clearance and increasing their conversion to beta-VLDL during lipolytic processing.
Chappell
D A
DA
Department of Internal Medicine, University of California, San Francisco 94140-0608.
D000328:Adult; D001667:Binding, Competitive; D005591:Chemical Fractionation; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood / Q000209:etiology*; D008079:Lipoproteins, VLDL / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011498:Protein Precursors / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000032:analysis; D011973:Receptors, LDL / Q000032:analysis
D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C036053:VLDL receptor; D006493:Heparin