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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2608.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Novel Inhibitor of Oxidosqualene:Lanosterol Cyclase Inhibits Very Low–Density Lipoprotein Apolipoprotein B100 (ApoB100) Production and Enhances Low-Density Lipoprotein ApoB100 Catabolism Through Marked Reduction in Hepatic Cholesterol Content

Dawn E. Telford; Sara M. Lipson; P. Hugh R. Barrett; Brian G. Sutherland; Jane Y. Edwards; Johannes D. Aebi; Henrietta Dehmlow; Olivier H. Morand; Murray W. Huff

From the Robarts Research Institute, Vascular Biology Group (D.E.T., S.M.L., B.G.S., J.Y.E., M.W.H.); Departments of Medicine (D.E.T., J.Y.E., M.W.H.) and Biochemistry (S.M.L., M.W.H.), The University of Western Ontario, London, Canada; the School of Medicine and Pharmacology (P.H.R.B.), University of Western Australia, Perth, West Australia, Australia; and the Pharmaceuticals Division (J.D.A., H.D., O.H.M.), F. Hoffmann-La Roche Ltd, Basel, Switzerland. O.H.M.’s current address: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, CH, 4123, Switzerland.

Correspondence to Dr Murray W. Huff, Robarts Research Institute, Room 416, 100 Perth Dr, London, Ontario, Canada, N6A 5K8. E-mail mhuff{at}uwo.ca

Objective— Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an enzyme in the cholesterol synthesis pathway, has the unique ability to inhibit cholesterol synthesis while simultaneously enhancing oxysterol synthesis. Our objectives were to determine, in vivo, if a novel OSC inhibitor reduced low-density lipoprotein (LDL) cholesterol and to define the mechanism(s) involved.

Methods and Results— Miniature pigs received the OSC inhibitor RO0717625 or placebo and a diet containing fat (34% of energy) and 400 mg per day of cholesterol. Treatment decreased plasma total cholesterol (–20%) and LDL cholesterol (–29%). Apolipoprotein B (apoB) kinetic parameters were determined. Very low–density lipoprotein (VLDL) apoB pool size decreased 22% because of inhibition of VLDL production (–43%). LDL apoB pool size decreased 22% because of a 1.5-fold increase in fractional catabolic rate (FCR). The increased FCR was associated with a 2-fold increase in hepatic LDL receptor mRNA. Hepatic total and microsomal cholesterol were reduced by 16% and 27%, respectively. Plasma lathosterol concentrations decreased 57%, reflecting inhibition of hepatic cholesterol synthesis. Treatment reduced plasma plant sterols and decreased postprandial cholesterol transport in chylomicrons.

Conclusions— A novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and enhanced LDL clearance. Thus, OSC represents a potential therapeutic target for dyslipidemia.

In miniature pigs, a novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and increased LDL receptor–mediated LDL apoB clearance. Cholesterol synthesis and postprandial cholesterol transport in chylomicrons decreased, resulting in a marked reduction in hepatic cholesterol concentration. Thus, OSC is a potential therapeutic target for dyslipidemia.

Key Words: oxidosqualene:lanosterol cyclase • apoB kinetics • LDL receptor • ABCG5 • ABCG8

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