Etofibrate increases binding of low and high density lipoprotein to human platelets of patients with Type II hyperlipoproteinemia

Abstract

Previous work suggested an influence of etofbrate, a diester of nicotinic acid and clolibric acid, on lipoprotein receptors. Besides its beneficial effects on plasma lipoprotein levels of decrease in total cholesterol, LDL-cholesterol and triglycerides and increase in HDL-cholesterol, etofibrate was shown to inhibit platelet function. In order to further evaluate platelet-lipoprotein interactions, the effects of etofibrate on plasma lipids and lipoproteins on the specific binding of normal [ 111In]LDL and [ 111In]HDL onto platelets as well as its effect on platelet function were evaluated in 8 patients affected by Type II hyperlipoproteinemia (HLP). In all patients binding was saturable and indicated high affinity binding sites capable of binding 927 ± 233 ng protein of [ 111In]LDL/10 9 platelets (Kd 12 ± 3 μg protein/ml) and 1496 ± 435 ng protein of [ 111In]HDL/10 9 platelets (K d14 ± 3 μg protein/ml). The capacity of native LDL (HDL) to displace bound [ 111In] LDL ([ 111In] HDL) by half (IC 50) amounted to 22 ± 9 μg protein/ml (26 ± 8 μg protein/ml). Following a 6-week treatment period with etofibrate (500 mg twice daily), decrease in plasma total cholesterol, LDL-cholesterol and apolipoprotein (apo) B and increase in HDL-cholesterol and apo AI was correlated to a significant ( P < 0.01) increase in LDL- as well as HDL-receptor binding. The platelet binding capacity increased to 1085 ± 212 ng protein/10 9 platelets (K d8 ± 3 μg protein/ml) for [ 111In]LDL and to 1867 ± 266 ng protein/10 9 platelets for [ 111In]HDL (K d 11 ± 3 μg protein/ml). Platelet function studies demonstrated significantly ( P < 0.01) reduced platelet aggregation in response to ADP and thromboxane formation after 6 weeks of etofibrate therapy. These findings in patients with HLP Type II indicate in vivo upregulation of specific [ 111In]LDL as well as [ 111In]HDL binding sites on human platelets associated with reduced platelet activation following etofibrate therapy.