Effects of vitamin E and HMG-CoA reductase inhibition on cholesteryl ester transfer protein and lecithin-cholesterol acyltransferase in hypercholesterolemia.
BACKGROUND
The enzyme lecithin-cholesterol acyl transferase (LCAT) esterifies free cholesterol on high-density lipoprotein (HDL) and the cholesteryl ester transfer protein (CETP) transfers cholesteryl ester to very-low-density lipoprotein (VLDL) and low-density lipoproteins (LDL). Using statins, contradictory findings have been made regarding CETP activity in normolipidemic individuals and in those with familial dysbetalipoproteinemia. In contrast, LCAT activity appears to be unaffected by simvastatin. Antioxidants have also been proposed for the use of anti-atherosclerotic treatment, because the oxidation of LDL may have a key role in the pathophysiology of atherogenesis.


OBJECTIVE
To investigate, in hypercholesterolemic patients, whether a combination of pravastatin with the antioxidant, vitamin E, has greater effects on the activity of CETP and of LCAT than does pravastatin alone.


METHODS
This placebo-diet-controlled multicenter trial included 220 hypercholesterolemic patients who were assigned randomly to groups to receive: diet and 20-40 mg pravastatin (n = 52), diet and alpha-tocopherol (n = 60), or diet associated with placebo (n = 52). Plasma LCAT activity was determined using excess exogenous substrate, containing [3H]cholesterol. Plasma CETP activity was measured in the supernatant fraction after precipitation of endogenous apo B-containing lipoproteins with phosphotungstate-Mg2+. The exchange of cholesteryl esters between [14C]cholesteryl ester-labeled LDL and unlabeled HDL was measured during a 16-h incubation, while LCAT was inhibited.


RESULTS
The addition of pravastatin to the diet induced a significant decrease in plasma CETP activity (P < 0.05); this effect was less evident in the group cotreated with vitamin E. For the first time, it was shown that CETP concentrations increased significantly after vitamin E alone (P < 0.05). No significant differences in the plasma activity of LCAT were observed among the groups.


CONCLUSIONS
Pravastatin reduced CETP activity, but not that of LCAT. Addition of vitamin E prevented the decrease in CETP activity and had no effect on LCAT activity. The mechanism responsible for these effects is unknown, but could involve the prevention of radical-induced damage to CETP by vitamin E.
Napoli
C
C
Department of Clinical and Experimental Medicine, University of Naples, Italy.
Leccese
M
M
Palumbo
G
G
de Nigris
F
F
Chiariello
P
P
Zuliani
P
P
Somma
P
P
Di Loreto
M
M
De Matteis
C
C
Cacciatore
F
F
Abete
P
P
Liguori
A
A
Chiariello
M
M
D'Armiento
F P
FP
D000975:Antioxidants / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D006023:Glycoproteins; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000097:blood* / Q000178:diet therapy / Q000188:drug therapy; D008297:Male; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood*; D017035:Pravastatin / Q000008:administration & dosage*; D014810:Vitamin E / Q000008:administration & dosage*
D000975:Antioxidants; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014810:Vitamin E; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D017035:Pravastatin