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Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects

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      Abstract

      Hyperlipidemic patients often have an accelerated esterified cholesterol transfer (ECT) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). We investigated the effect of simvastatin on ECT in twelve normolipidemic subjects. After 6 weeks of simvastatin administration, ECT was decreased by 23%. To determine the mechanism of action of simvastatin, we measured ECT in different recombination experiments, using an isotopic assay in which the transfer of labelled EC from HDL to VLDL/LDL was determined. When HDL of the treated subjects were incubated with VLDL/LDL and CETP fractions isolated from control plasma, no effect of simvastatin was observed, indicating that the drug did not alter the HDL-dependent ECT. This might be expected since simvastatin induced only minor modifications of HDL structure. When HDL and VLDL/LDL of control plasma were incubated with CETP fractions of the treated subjects, a clear reduction of ECT occurred after simvastatin administration. The decrease of plasma transfer activity was correlated to that of CETP concentration and accounted for the simvastatin-induced lowering of ECT. The diminution of plasma CETP was correlated to that of the apo B-containing lipoproteins concentration. This finding confirms previous reports suggesting a relationship between LDL level and CETP activity. In conclusion, our work shows that simvastatin administration results in a decrease of ECT and that this effect occurs through a lowering of plasma CETP activity.

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      References

        • Glomset J.A.
        The plasma lecithin: cholesterol acyltransferase reaction.
        J. Lipid Res. 1968; 9: 155
        • Miller N.E.
        • Laville A.
        • Crook D.
        Direct evidence that reverse cholesterol transport is mediated by high density lipoprotein in the rabbit.
        Nature. 1985; 314: 109
        • Tall A.R.
        Plasma high density lipoproteins: metabolism and relationship to atherogenesis.
        J. Clin. Invest. 1990; 86: 379
        • Tall A.R.
        Plasma lipid transfer proteins.
        J. Lipid Res. 1986; 27: 361
        • Fielding C.J.
        • Reaven G.M.
        • Liu G.
        • Fielding P.E.
        Increase free cholesterol in plasma low and very low density lipoproteins in non insulin-dependent diabetes mellitus: its role in the inhibition of cholesteryl ester transfer.
        in: Proc. Natl. Acad. Sci. USA. 81. 1984: 2512
        • Fielding P.E.
        • Fielding C.J.
        • Havel R.J.
        • Kane J.P.
        • Tun P.
        Cholesterol net transport, esterification and transfer in human hyperlipidemic plasma.
        J. Clin. Invest. 1983; 71: 449
        • Tall A.R.
        • Granot E.
        • Brocia R.
        • Tabas I.
        • Hesler C.
        • Williams K.
        • Denke M.
        Accelerated transfer of cholesteryl esters in dyslipidemic plasma. Role of cholesterol ester transfer protein.
        J. Clin. Invest. 1987; 79: 1217
        • Mann C.J.
        • Yen F.T.
        • Grant A.M.
        • Bihain B.E.
        Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.
        J. Clin. Invest. 1991; 88: 2059
        • Bagdade J.D.
        • Ritter M.E.
        • Subbaiah P.V.
        Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia.
        J. Clin. Invest. 1991; 87: 1259
        • Dullaart R.P.F.
        • Groener J.E.M.
        • Dikkeschei L.D.
        • Erkelens D.W.
        • Doorenbos H.
        Increased cholesteryl ester transfer activity in complicated type I (insulindependent) diabetes mellitus. Its relationship with serum lipids.
        Diabetologia. 1989; 32: 14
        • Son Y.C.
        • Zilversmit D.B.
        Increased lipid transfer activities in hyperlipidemic rabbit plasma.
        Arteriosclerosis. 1986; 6: 345
        • Tall A.R.
        • Sammet D.
        • Granot E.
        Mechanisms of enhanced cholesteryl ester transfer from high density lipoproteins to apolipoprotein B-containing lipoproteins during alimentary lipemia.
        J. Clin. Invest. 1986; 77: 1163
        • Morton R.E.
        • Zilversmit D.B.
        A plasma inhibitor of triglyceride and cholesteryl ester transfer activities.
        J. Biol. Chem. 1981; 256: 11992
        • Morton R.E.
        Binding of plasma-derived lipid transfer protein to lipoprotein substrates.
        J. Biol. Chem. 1985; 260: 12593
        • Marcel Y.L.
        • Vezina C.
        • Teng B.
        • Sniderman A.
        Transfer of cholesterol esters between human high-density lipoproteins and triglyceride-rich lipoproteins controlled by a plasma protein factor.
        Atherosclerosis. 1980; 35: 127
        • Barter P.J.
        • Hopkins G.J.
        • Calvert G.D.
        Transfers and exchanges of esterified cholesterol between plasma lipoproteins.
        Biochem. J. 1982; 208: 1
        • Dullaart R.P.F.
        • Groener J.E.M.
        • Erkelens D.W.
        Effect of the composition of very low and low density lipoproteins on the rate of cholesteryl ester transfer from high density lipoproteins in man, studied in vitro.
        Eur. J. Clin. Invest. 1987; 17: 241
        • Morton R.E.
        • Steinbrunner J.V.
        Concentration of neutral lipids in the phospholipid surface of substrate particles determines lipid transfer protein activity.
        J. Lipid Res. 1990; 3: 1559
        • Franceschini G.
        • Maderna P.
        • Sirtori C.R.
        Reverse cholesterol transport: physiology and pharmacology.
        Atherosclerosis. 1991; 88: 99
        • Abbey M.
        • Clifton P.
        • Kestin M.
        • Belling B.
        • Nestel P.
        Effect of fish oil on lipoproteins, lecithin: cholesterol acyl transferase and lipid transfer protein activity in humans.
        Arteriosclerosis. 1990; 10: 85
        • Franceschini G.
        • Sirtori M.
        • Vaccarino V.
        • Giafranceschi G.
        • Rezzonico L.
        • Chiesa G.
        • Sirtori C.R.
        Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer.
        Arteriosclerosis. 1989; 9: 462
        • Bagdade J.D.
        • Kaufman D.
        • Ritter M.C.
        • Subbaiah P.V.
        Probucol treatment in hypercholesterolemic patients: effects on lipoprotein composition, HDL particle size and cholesteryl ester transfer.
        Atherosclerosis. 1990; 84: 145
        • Moulin P.
        • Bourdillon M.C.
        • De Parscau L.
        • Perrot L.
        • Ponsin G.
        • Berthezene F.
        High density lipoprotein alterations induced by bezafibrate in healthy male volunteers.
        Atherosclerosis. 1987; 67: 17
        • Bhatnagar D.
        • Durrington P.N.
        • MacKness M.I.
        • Arrol S.
        • Winocour P.H.
        • Prais H.
        Effects of treatment of hypertriglyceridaemia with gemfibrozil on serum lipoproteins and the transfer of cholesteryl ester from high density lipoproteins to low density lipoproteins.
        Atherosclerosis. 1992; 92: 49
        • Bagdade J.D.
        • Lane J.T.
        • Stone N.
        • Ritter M.C.
        • Subbaiah P.V.
        Persistent abnormalities in lipoprotein composition and cholesteryl ester transfer following lovastatin treatment.
        J. Lipid Res. 1990; 31: 1263
        • Kostner G.M.
        • Avogaro P.
        • Bittolo-Bon G.
        • Gazzoloto G.
        The determination of high density lipoproteins in the lipoprotein laboratory, Screening methods compared.
        Clin. Chem. 1979; 25: 939
        • Friedewald W.T.
        • Levy R.
        • Fredrickson D.S.
        Estimation of concentration of LDL cholesterol without the use of preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499
        • Perrot L.
        • Berthezene F.
        Dosages radioimmunologiques des apolipoproteines A-1 et A-II.
        Lyon Med. 1981; 20: 441
        • Karlin J.B.
        • Juhn D.J.
        • Scanu A.M.
        • Rubenstein A.H.
        Measurement of serum apolipoprotein B by radioimmunoassay.
        Eur. J. Clin. Invest. 1978; 8: 19
        • Prendergast F.G.
        • Hangland R.P.
        • Callahan P.J.
        1(4-(Trimethyl-amino)phenyl)-6-phenylhexa-1,3,5-triene: synthesis, fluorescence properties and use as a fluorescence probe of lipid bilayers.
        Biochemistry. 1981; 20: 7333
        • Tollefson J.H.
        • Albers J.J.
        Isolation, characterization and assay of plasma lipid transfer proteins.
        Methods Enzymol. 1986; 129: 797
        • Groener J.E.M.
        • Van Rozen A.J.
        • Erkelens D.W.
        Cholesteryl ester transfer activity. Localization and role in distribution of cholesteryl ester among lipoproteins in man.
        Atherosclerosis. 1984; 50: 261
        • Swenson T.L.
        • Hesler C.B.
        • Brown M.L.
        • et al.
        Mechanism of cholesteryl ester transfer protein inhibition by a neutralizing monoclonal antibody and mapping of the monoclonal antibody epitope.
        J. Biol. Chem. 1989; 264: 14318
        • Morton R.E.
        Free cholesterol is a potent regulator of lipid transfer protein function.
        J. Biol. Chem. 1988; 263: 12235
        • McPherson R.
        • Mann C.J.
        • Tall A.R.
        • Hogue H.
        • Martin L.
        • Milne R.W.
        • Marcel Y.L.
        Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia: relation to cholesteryl ester transfer protein activity and other lipoprotein variables, Arterioscler.
        Arterioscler. Thromb. 1991; 11: 797
        • Inazu A.
        • Brown M.L.
        • Hesler C.B.
        • et al.
        Increased high-density lipoprotein levels caused by a common cholesteryl ester transfer protein gene mutation.
        N. Engl. J. Med. 1990; 323: 1234
        • Quig D.W.
        • Zilversmit D.B.
        Dissociation between cholesterol secretion and plasma lipid transfer activity in rabbits.
        FASEB J. 1988; 2: 2712
        • Warren R.J.
        • Ebert D.L.
        • Barter P.J.
        • Mitchell A.
        The regulation of hepatic lipase and cholesteryl ester transfer protein activity in the cholesterol fed rabbit.
        Biochim. Biophys. Acta. 1991; 1086: 354
        • Stein Y.
        • Dabach Y.
        • Hollander G.
        • Stein O.
        Cholesteryl ester transfer activity in hamster plasma: increase by fat and cholesterol rich diets.
        Biochim. Biophys. Acta. 1990; 1042: 138
        • Quig D.W.
        • Arbeeny C.M.
        • Zilversmit D.B.
        Effects of hyperlipidemias in hamsters on lipid transfer protein activity and unidirectional cholesteryl ester transfer in plasma.
        Biochim. Biophys. Acta. 1991; 1083: 257
        • Quinet E.
        • Tall A.
        • Ramakrishnan R.
        • Rudel L.
        Plasma lipid transfer protein as a determinant of the atherogenicity of monkey plasma lipoproteins.
        J. Clin. Invest. 1991; 87: 1559