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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1910-1917.)
© 1997 American Heart Association, Inc.

Articles

Lovastatin Decreases De Novo Cholesterol Synthesis and LDL Apo B-100 Production Rates in Combined-Hyperlipidemic Males

Marina Cuchel; Ernst J. Schaefer; John S. Millar; Peter J.H. Jones; Gregory G. Dolnikowski; Carlo Vergani; ; Alice H. Lichtenstein

From the Lipid Research Laboratory, Division of Endocrinology, Metabolism and Molecular Medicine, New England Medical Center, Boston (M.C., J.S.M., E.J.S., G.G.D., A.H.L.); the School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada (P.J.H.J.); and the Cattedra di Gerontologia e Geriatria, Istituto di Medicina Interna, Universitá degli Studi, Milan, Italy (C.V.).

Correspondence to Dr. Alice H. Lichtenstein, New England Medical Center, NEMC Box 216, Boston, MA 02111. E-mail lichtenst_li{at}hnrc.tufts.edu

Abstract The effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, on the kinetics of de novo cholesterol synthesis and apolipoprotein (apo) B in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) was investigated in five male patients with combined hyperlipidemia. Subjects were counseled to follow a Step 2 diet and were treated with lovastatin and placebo in randomly assigned order for 6-week periods. At the end of each experimental period, subjects were given deuterium oxide orally and de novo cholesterol synthesis was assessed from deuterium incorporation into cholesterol and expressed as fractional synthesis rate (C-FSR) and production rate (C-PR). Simultaneously, the kinetics of VLDL, IDL, and LDL apo B-100 were studied in the fed state using a primed-constant infusion of deuterated leucine to measure fractional catabolic rates (FCR) and production rates (PR). Drug treatment resulted in significant decreases in total cholesterol (-29%), VLDL cholesterol (-40%), LDL cholesterol (-27%), and apo B (-16%) levels and increases in HDL cholesterol (+13%) and apolipoprotein (apo) A-I (+11%) levels. Associated with these plasma lipoprotein responses was a significant reduction in both de novo C-FSR (-40%; P=.04) and C-PR (-42%; P=.03). Treatment with lovastatin in these patients had no significant effect on the FCR of apoB-100 in VLDL, IDL, or LDL, but resulted in a significant decrease in the PR of apoB-100 in IDL and LDL. Comparing the kinetic data of these patients with those of 10 normolipidemic control subjects indicates that lovastatin treatment normalized apoB-100 IDL and LDL PR. The results of these studies suggest that the declines in plasma lipid levels observed after treatment of combined hyperlipidemic patients with lovastatin are attributable to reductions in the C-FSR and C-PR of de novo cholesterol synthesis and the PR of apoB-100 containing lipoproteins. The decline in de novo cholesterol synthesis, rather than an increase in direct uptake of VLDL and IDL, may have contributed to the decline in the PR observed.

Key Words: lovastatin • cholesterol • kinetics • lipoproteins • hyperlipidemia • fractional catabolic rate • production rate • apo B-100

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