Mechanisms of high-density lipoprotein reduction after probucol treatment: changes in plasma cholesterol esterification/transfer and lipase activities.
Probucol treatment results in a significant reduction of plasma high-density lipoprotein (HDL) levels. Since the remodeling of HDL within the plasma compartment is a crucial determinant of HDL levels, the activities of several factors participating in the process, ie, lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and lipoprotein and hepatic lipases (LPL, HL), were evaluated in 15 hypercholesterolemic patients treated with probucol (1 g/d) for 8 weeks. Drug treatment was associated with significant reductions of HDL cholesterol ([HDL-C] -32%), HDL2-C (-65%), HDL3-C (-22%), apolipoprotein (apo)A-I (-27%), and apo A-II (-11%) levels and with the accumulation of small HDL in plasma. CETP activity increased by 48%, with minor changes in LCAT (-7%), LPL (+4%), and HL (-7%) activities. By linear regression analysis, CETP activity correlated inversely with HDL-C, HDL2-C, and apo A-I levels (r = -.63, -.52, and -.73, respectively) and with HDL particle size. In multivariate analysis, CETP activity was the strongest predictor of HDL-C levels, apo A-I levels, and HDL particle size. The hypothetical mechanism of probucol is a stimulation of CETP activity, resulting in the formation of triglyceride (TG)-enriched HDL. These are acted on by HL, leading to the accumulation of small HDL in plasma.
Chiesa
G
G
Center E. Grossi Paoletti, Institute of Pharmacological Sciences, University of Milano, Italy.
Michelagnoli
S
S
Cassinotti
M
M
Gianfranceschi
G
G
Werba
J P
JP
Pazzucconi
F
F
Sirtori
C R
CR
Franceschini
G
G
D016632:Apolipoprotein A-I / Q000032:analysis; D002352:Carrier Proteins / Q000097:blood*; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000097:blood*; D005260:Female; D006023:Glycoproteins; D006801:Humans; D008049:Lipase / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D011341:Probucol / Q000097:blood / Q000494:pharmacology*
D016632:Apolipoprotein A-I; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; D011341:Probucol