ETOFIBRATE INCREASES BINDING OF LOW AND HIGH-DENSITY-LIPOPROTEIN TO HUMAN PLATELETS OF PATIENTS WITH TYPE-II HYPERLIPOPROTEINEMIA

Previous work suggested an influence of etofibrate, a diester of nicot inic acid and clofibric acid, on lipoprotein receptors. Besides its be neficial effects on plasma lipoprotein levels of decrease in total cho lesterol, LDL-cholesterol and triglycerides and increase in HDL-choles terol, etofibrate was shown to inhibit platelet function. In order to further evaluate platelet-lipoprotein interactions, the effects of eto fibrate on plasma lipids and lipoproteins on the specific binding of n ormal [In-111]LDL and [In-111]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 [In-111]LDL/10(9) platelets (K(d) 12 +/- 3 mug protein/m l) and 1496 +/- 435 ng protein of [In-111]HDL/10(9) platelets (K(d) 14 +/- 3 mug protein/ml). The capacity of native LDL (HDL) to displace b ound [In-111]LDL ([In-111]HDL) by half (IC50) amounted to 22 +/- 9 mug protein/ml (26 +/- 8 mug protein/ml). Following a 6-week treatment pe riod with etofibrate (500 mg twice daily), decrease in plasma total ch olesterol, 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(d) 8 +/- 3 mug protein/nil) for [In-111]LDL and to 1867 +/- 266 ng protein /109 platelets for [In-111]HDL (K(d) 11 +/- 3 mug protein/ml). Platele t function studies demonstrated significantly (P < 0.01) reduced plate let aggregation in response to ADP and thromboxane formation after 6 w eeks of etofibrate therapy. These findings in patients with HLP Type I I indicate in vivo upregulation of specific [In-111]LDL as well as [In -111]HDL binding sites on human platelets associated with reduced plat elet activation following etofibrate therapy.