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

• Published in: The Journal of biological chemistry 1994-03, Vol.269 (9), p.6645-6650
• Main Authors: BRADFUTE, D. L, SIMONI, R. D
• Format: Article
• Language: English
• Subjects: acetate ester; acetates esters; acetatos esteres; actividad enzimatica; activite enzymatique; Analytical, structural and metabolic biochemistry; Animals; arn mensajero; arn messager; beta-Galactosidase - biosynthesis; Biological and medical sciences; CHO Cells; cholesterol; Cholesterol - biosynthesis; colesterol; Cricetinae; degradacion; degradation; Enzymes and enzyme inhibitors; enzymic activity; Escherichia coli - enzymology; expresion genica; expression des genes; Fundamental and applied biological sciences. Psychology; gene expression; genetica; genetics; genetique; hamster; hamsters; Hydroxymethylglutaryl CoA Reductases - biosynthesis; Hydroxymethylglutaryl CoA Reductases - metabolism; Kinetics; Mesocricetus; messenger rna; metabolism; metabolisme; metabolismo; Oxidoreductases; oxidorreductasas; oxydoreductase; Polyisoprenyl Phosphates - metabolism; Polyisoprenyl Phosphates - pharmacology; Protein Biosynthesis - drug effects; protein synthesis; proteinas; proteine; proteins; Recombinant Fusion Proteins - biosynthesis; RNA, Messenger - biosynthesis; Sesquiterpenes; sintesis de proteinas; synthese proteique; Time Factors; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)37422-7

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 microgram/ml (37.8 micrometer), 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.