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.
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.
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.forename: Utako
authors.initials: U
authors.lastname: Seino
authors.forename: Osamu
authors.initials: O
authors.lastname: Miyazaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Hanyu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirayama
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Saito
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Suguru
authors.initials: S
authors.lastname: Akamatsu
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Nakano
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Nakajima
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Okazaki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Okada
mesh_terms: D000328:Adult; D000368:Aged; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011341:Probucol / Q000494:pharmacology*
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000924:Anticholesteremic Agents; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D010743:Phospholipids; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; C410382:LIPG protein, human; D008049:Lipase; D011341:Probucol