EFFECT OF APOLIPOPROTEIN-E VARIANTS ON LIPOLYSIS OF VERY-LOW-DENSITY LIPOPROTEINS BY HEPARAN-SULFATE PROTEOGLYCAN-BOUND LIPOPROTEIN-LIPASE

Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (H SPG) at the luminal surface of endothelium. It is the key enzyme invol ved in the hydrolysis of very low density lipoproteins (VLDL). Prior t o lipolysis by LPL, the lipoproteins are considered to interact with v essel wall HSPG. Apolipoprotein (ape) E is thought to mediate this int eraction thereby enhancing the stability of the lipoprotein-LPL comple x. We hypothesize that apo E mutations may cause a diminished interact ion of VLDL with HSPG leading to impaired lipolysis of VLDL by HSPG-bo und LPL. In order to test this hypothesis, lipolysis experiments were performed using HSPG-bound LPL. The mean lipolysis rates of VLDL, isol ated from the apo E2 (Lys(146) -->Gln) heterozygotes, apo E2 (Arg(158) -->Cys) homozygotes and apo E3-Leiden heterozygotes were 92.3 +/- 10.3 (ns), 77.3 +/- 4.2 (P < 0.05) and 76.7 +/- 10.0% (P < 0.05), respecti vely, of that of control VLDL (100.0 +/- 9.7%). No differences in lipo lysis were observed between VLDL from controls and VLDL from the same patients if LPL in solution was used. Thus, compositional differences alone can not explain the differences in lipolysis rates observed with HSPG-bound LPL. In competition experiments, the binding efficiency to HSPG-LPL of VLDL from the apo E2 (Lys(146)-->Gln) heterozygotes, apo E2 (Arg(158)-->Cys) homozygotes and apo E3-Leiden heterozygotes was 63 (ns), 41 (P < 0.05) and 35% (P < 0.05), respectively of that of contr ol VLDL (100%). We conclude that VLDL isolated from apo E2 homozygotes and apo E3-Leiden heterozygotes display decreased lipolysis by HSPG-b ound LPL due to a defective binding of these lipoproteins to the HSPG- LPL complex. (C) 1998 Elsevier Science Ireland Ltd.