Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding.
Heterozygotes for familial defective apolipoprotein B-100 (FDB) have two populations of low density lipoprotein (LDL), one bearing normal apolipoprotein B-100 (apo B) and the other bearing defective apo B which exhibits a much lower affinity for the LDL-receptor. If HMGCoA reductase inhibitors such as simvastatin lowered LDL mainly by up-regulating LDL-receptor mediated clearance, they should decrease the overall binding affinity of LDL from an FDB heterozygote by selectively decreasing LDL bearing normal apo B. We compared how LDL from FDB heterozygotes competed with normal 125I-labelled LDL for binding to LDL-receptors while on and off therapy with simvastatin. The LDL of FDB heterozygotes had 40% (n = 10) the affinity of normal LDL (n = 12) for the LDL receptor on cultured fibroblasts, and 55% (n = 6) of normal LDL (n = 6) for that on HepG2 cells. Treatment of FDB subjects with simvastatin (n = 10) decreased serum LDL by 22% but had no effect on its binding affinity for LDL receptors, indicative of lowering of LDL containing both normal and defective apo B. This is consistent with the major LDL lowering effect being associated with decreased synthesis of LDL, rather than enhanced LDL-receptor clearance.
Mamotte
C D
CD
Department of Biochemistry, Royal Perth Hospital, Australia.
Sturm
M
M
Foo
J I
JI
van Bockxmeer
F M
FM
Taylor
R R
RR
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001055:Apolipoproteins B / Q000235:genetics*; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D003327:Coronary Disease / Q000150:complications; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism*; D019821:Simvastatin; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin