HDL biology
Probucol lowers ANGPTL3 and large-HDL phospholipids while raising prebeta1-HDL in hypercholesterolemic patients (Atherosclerosis 2008)
Original title: Probucol markedly reduces HDL phospholipids and elevated prebeta1-HDL without delayed conversion into alpha-migrating HDL: putative role of angiopoietin-like protein 3 in probucol-induced HDL remodeling
Because probucol, a unique hypolipidemic drug that increases CETP activity, lowers HDL cholesterol and raises prebeta1-HDL (lipid-poor HDL), researchers tested whether it also lowers angiopoietin-like protein 3 (ANGPTL3), which promotes HDL phospholipid hydrolysis, in 39 hypercholesterolemic patients before and after 4 weeks of treatment. Median ANGPTL3 fell from 143 to 113 ug/L (p<0.05), and probucol reduced phospholipid content of very large HDL particles by 65% (p<0.01) and large HDL particles by 53% (p<0.001). The change in ANGPTL3, but not in CETP mass, correlated positively with the change in large-HDL phospholipids (r=0.455, p<0.05). Absolute and relative prebeta1-HDL concentrations rose 14% (p<0.01) and 60% (p<0.001), respectively, while the rate of prebeta1-HDL conversion to alpha-migrating HDL by LCAT did not change. The authors conclude probucol lowers plasma ANGPTL3 and HDL phospholipids while raising prebeta1-HDL, likely via an endothelial-lipase-mediated pathway.
Original abstract
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 prebeta1-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 prebeta1-HDL. To determine whether probucol decreases ANGPTL3 and HDL phospholipids while increasing prebeta1-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 microg/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 prebeta1-HDL increased by 14% (p<0.01) and 60% (p<0.001), respectively. The conversion rate of prebeta1-HDL into alpha-migrating HDL by lecithin-cholesterol acyltransferase did not change significantly. In conclusion, probucol decreases plasma ANGPTL3 and HDL phospholipids while increasing prebeta1-HDL. We speculate that probucol induces HDL remodeling via an endothelial lipase-mediated pathway.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.