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Vol. 289, Issue 1, 85-92, April 1999

Effects of LY295427, a Low-Density Lipoprotein (LDL) Receptor Up-Regulator, on LDL Receptor Gene Transcription and Cholesterol Metabolism in Normal and Hypercholesterolemic Hamsters1

William R. Bensch, Robert A. Gadski, James S. Bean, Lisa S. Beavers, Robert J. Schmidt, David N. Perry, Anthony T. Murphy, Donald B. McClure, Patrick I. Eacho, Alan P. Breau, Robert A. Archer and Raymond F. Kauffman

Divisions of Cardiovascular Research (W.R.B., J.S.B., R.J.S., D.N.P., P.I.E., R.A.A., R.F.K.), Endocrine Research (R.A.G., L.S.B.), Drug Disposition (A.T.M., A.P.B.), and Research Technologies and Proteins (D.B.M), Eli Lilly and Company, Indianapolis, Indiana

The action of LY295427 [(3alpha ,4alpha ,5alpha )-4-(2-propenylcholestan-3-ol)], a compound that derepresses low-density lipoprotein receptor (LDL-R) expression in a cell-based model, was examined in hamsters. It was found that the compound does not have an effect in normal chow-fed hamsters, in which LDL-R levels are not repressed, but exerts a marked hypocholesterolemic effect (>70% decrease) in cholesterol-coconut oil-fed hamsters, in which LDL-R is repressed. In this model, there is a dose-response for cholesterol lowering with an approximate ED50 value of 40 mg/kg/day and an inverse relationship between serum cholesterol and serum LY295427 levels. LDL-R mRNA is increased (2-fold) and liver cholesterol ester content is decreased (>90%). Unlike the 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor lovastatin, the decreased serum cholesterol is confined to the non-high-density lipoprotein fraction. Furthermore, LY295427 does not affect cholesterol biosynthesis, and it does not have a significant effect on cholesterol absorption. These data suggest that LY295427 acts in the hypercholesterolemic hamster by derepressing LDL-R transcription, thereby enhancing cholesterol clearance from the blood. The results with LY295427 suggest that compounds that act to increase LDL-R may represent a novel approach in the pharmacotherapy for hypercholesterolemia.

0022-3565/99/2891-0085$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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