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Journal of Lipid Research, Vol. 43, 1464-1471, September 2002
Copyright © 2002 by Lipid Research, Inc.

Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia

Jeffrey S. Cohn^1,*, Michel Tremblay^*, Rami Batal^*, Hélène Jacques^*, Lyne Veilleux^*, Claudia Rodriguez^*, P. Hugh R. Barrett, Denise Dubreuil^*, Madeleine Roy^*, Lise Bernier^*, Orval Mamer and Jean Davignon^*

^* Hyperlipidemia and Atherosclerosis Research Group, Montréal, Québec, Canada
McGill University Biomedical Mass Spectrometry Unit, Montréal, Québec, Canada
Department of Medicine, University of Western Australia and the Western Australia Institute for Medical Research, Perth, Australia

¹ To whom correspondence should be addressed. e-mail: cohnj{at}ircm.qc.ca

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30–37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 ± 0.9 to 4.3 ± 0.2 mg/dl (-38 ± 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 ± 0.8 vs. 1.7 ± 0.2 mg/dl; -42 ± 11%) and IDL/LDL apoE (1.9 ± 0.3 vs. 0.8 ± 0.1 mg/dl; -57 ± 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 ± 0.39 to 3.04 ± 0.51 mg/kg/day (-34 ± 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 ± 0.67 to 2.26 ± 0.42 mg/kg/day (-36 ± 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6).

Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.

Abbreviations: apo, apolipoprotein; FPLC, fast protein-liquid chromatography; FTR, fractional transport rate; GC-MS, gas chromatography-mass spectrometry; IEF, isoelectric focusing; RT, residence time; TR, transport rate

Supplementary key words triglyceride • cholesterol • atherosclerosis • statin • stable isotope • metabolism

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