Non-sterol compounds that regulate cholesterogenesis. Analogues of farnesyl pyrophosphate reduce 3-hydroxy-3-methylglutaryl-coenzyme A reductase levels.

Abstract

Farnesyl acetate and ethyl farnesyl ether, two analogues of farnesyl pyrophosphate, stimulate post-transcriptional down-regulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthesis of cholesterol and isoprenoids. Farnesyl acetate and ethyl farnesyl ether reduce translation of HMG-CoA reductase mRNA and enhance degradation of the enzyme, the same regulatory effects attributed to the putative non-sterol regulatory metabolite (Goldstein, J.L., and Brown, M.S. (1990) Nature 343, 425-430). HMGal, a fusion protein consisting of the membrane domain of HMG-CoA reductase linked to Escherichia coli beta-galactosidase, is subject to the same regulated degradation as HMG-CoA reductase (Skalnik, D. G., Narita, H., Kent, C., and Simoni, R. D. (1988) J. Biol. Chem. 263, 6836-6841). At 10 micrograms/ml (37.8 microM), farnesyl acetate and ethyl farnesyl ether trigger a 50-80% reduction in HMGal activity. Farnesyl acetate reduces the synthesis of HMG-CoA reductase and HM-Gal by 60-80%, but neither farnesyl compound affects HMG-CoA reductase mRNA levels. Farnesyl acetate and ethyl farnesyl ether stimulated the degradation of HMG-CoA reductase and HMGal, reducing the half-lives of the enzymes by 40-70%. In addition to their regulatory effects on HMG-CoA reductase, these farnesyl compounds also directly disrupt sterol synthesis.