Abstract
The action of LY295427 [(3α,4α,5α)-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.
Footnotes
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Send reprint requests to: Dr. William R. Bensch, Cardiovascular Research, Drop Code 0522, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. E-mail:wrbensch{at}lilly.com
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↵1 A preliminary report of these results was presented at the Experimental Biology 1994 meeting (FASEB J8:A373).
- Abbreviations:
- HDL
- high-density lipoprotein
- HMG-CoA
- 3-hydroxy-3-methylglutarylcoenzyme A
- LDL
- low-density lipoprotein
- LDL-R
- low-density lipoprotein receptor
- SRE
- sterol regulatory element
- SREBP
- sterol regulatory element binding protein
- Received June 1, 1998.
- Accepted October 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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