Probucol markedly reduces HDL phospholipids and elevated preβ1-HDL without delayed conversion into α-migrating HDL: Putative role of angiopoietin-like protein 3 in probucol-induced HDL remodeling

Probucol is a unique hypolipidemic agent that increases cholesteryl ester transfer protein (CETP) activity. Enhanced CETP-mediated conversion of high-density lipoprotein (HDL) partly explains the probucol-induced decrease in HDL cholesterol and increase in plasma preβ1-HDL (native lipid-poor HDL) concentrations. However, HDL cholesterol is reduced in patients that are completely deficient in CETP. Angiopoietin-like protein 3 (ANGPTL3) is an endogenous suppressor of endothelial lipase that promotes the hydrolysis of HDL phospholipids and may generate preβ1-HDL. To determine whether probucol decreases ANGPTL3 and HDL phospholipids while increasing preβ1-HDL, we measured these parameters before and after a 4-week probucol treatment in 39 hypercholesterolemic patients and age- and sex-matched controls. The median ANGPTL3 had decreased from 143 to 113 μg/L by week 4 (p < 0.05). High-performance liquid chromatography revealed that probucol decreased the phospholipid content of very large (13.5–15 nm) and large (12.1 nm) HDL particles predominantly by 65% (p < 0.01) and 53% (p < 0.001), respectively. The change in ANGPTL3, but not CETP mass, was positively correlated with that in large HDL phospholipids (r = 0.455, p < 0.05). The absolute and relative concentrations of preβ1-HDL increased by 14% (p < 0.01) and 60% (p < 0.001), respectively. The conversion rate of preβ1-HDL into α-migrating HDL by lecithin-cholesterol acyltransferase did not change significantly. In conclusion, probucol decreases plasma ANGPTL3 and HDL phospholipids while increasing preβ1-HDL. We speculate that probucol induces HDL remodeling via an endothelial lipase-mediated pathway.