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Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding
C D Mamotte1, M Sturm, J I Foo
1Department of Biochemistry, Royal Perth Hospital, Australia.
Insights
Simvastatin treatment for familial defective apolipoprotein B-100 (FDB) lowers LDL cholesterol by reducing LDL synthesis, not by increasing LDL receptor clearance. This indicates simvastatin affects both normal and defective apo B production.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Familial defective apolipoprotein B-100 (FDB) is characterized by two low-density lipoprotein (LDL) populations: one with normal apolipoprotein B-100 (apo B) and another with defective apo B, showing reduced LDL receptor affinity.
- HMGCoA reductase inhibitors, like simvastatin, are known to lower LDL cholesterol. A key question is whether this occurs primarily through increased LDL receptor-mediated clearance or reduced LDL synthesis.
Purpose of the Study:
- To investigate the mechanism by which simvastatin lowers LDL cholesterol in FDB heterozygotes.
- To determine if simvastatin therapy alters the binding affinity of LDL from FDB heterozygotes to LDL receptors, which would indicate selective clearance of normal LDL.
Main Methods:
- Comparison of LDL binding affinity from FDB heterozygotes versus normal LDL to LDL receptors on cultured fibroblasts and HepG2 cells.
- Assessment of LDL binding affinity in FDB heterozygotes before and after simvastatin treatment.
Main Results:
- LDL from FDB heterozygotes exhibited significantly lower binding affinity to LDL receptors compared to normal LDL (40% on fibroblasts, 55% on HepG2 cells).
- Simvastatin treatment (22% decrease in serum LDL) did not alter the binding affinity of LDL from FDB heterozygotes.
- This lack of change in binding affinity suggests simvastatin reduces LDL levels by affecting both normal and defective apo B-containing LDL.
Conclusions:
- The primary mechanism of LDL cholesterol reduction by simvastatin in FDB heterozygotes is likely decreased LDL synthesis, rather than enhanced LDL receptor-mediated clearance.
- Simvastatin's effect is not selective for normal apo B-containing LDL, supporting a broader impact on LDL production.
Abstract:
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.