Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase.
Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the luminal surface of endothelium. It is the key enzyme involved in the hydrolysis of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the lipoproteins are considered to interact with vessel wall HSPG. Apolipoprotein (apo) E is thought to mediate this interaction thereby enhancing the stability of the lipoprotein-LPL complex. We hypothesize that apo E mutations may cause a diminished interaction of VLDL with HSPG leading to impaired lipolysis of VLDL by HSPG-bound LPL. In order to test this hypothesis, lipolysis experiments were performed using HSPG-bound LPL. The mean lipolysis rates of VLDL, isolated from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->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), respectively, of that of control VLDL (100.0 +/- 9.7%). No differences in lipolysis 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 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and apo E3-Leiden heterozygotes was 63 (ns), 41 (P < 0.05) and 35% (P < 0.05), respectively of that of control VLDL (100%). We conclude that VLDL isolated from apo E2 homozygotes and apo E3-Leiden heterozygotes display decreased lipolysis by HSPG-bound LPL due to a defective binding of these lipoproteins to the HSPG-LPL complex.
de Man
F H
FH
Department of Cardiology, University Hospital Leiden, The Netherlands.
de Beer
F
F
van de Laarse
A
A
Smelt
A H
AH
Leuven
J A
JA
Havekes
L M
LM
D000328:Adult; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood / Q000235:genetics; D066298:In Vitro Techniques; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D019812:Heparan Sulfate Proteoglycans; D008079:Lipoproteins, VLDL; D008071:Lipoprotein Lipase