POSTTRANSCRIPTIONAL REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE BY 3-BETA-HYDROXY-LANOST-8-EN-32-AL, AN INTERMEDIATE IN THE CONVERSION OF LANOSTEROL TO CHOLESTEROL

The lanosterol demethylation intermediate 3beta-hydroxy-lanost-8-en-32-al is a known suppressor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme of cholesterol biosynthesis. Studies on the mechanism of action of this compound have been hampered by its rapid metabolism. As one approach to this problem, the effects of 3beta-hydroxy-lanost-8-en-32-al on HMGR gene expression were examined using a mutant cell line which lacks lanosterol 14alpha-methyl demethylase activity. Data are presented which suggest that 3beta-hydroxy-lanost-8-en-32-al inhibits HMGR gene expression by reducing the translational efficiency of the HMGR mRNA. We have recently reported that 15alpha-fluoro-3beta-hydroxy-lanost-7-en-32-aldehyde, a compound which is structurally similar to 3beta-hydroxy-lanost-8-en-32-aldehyde, suppresses HMGR activity in cultured Chinese hamster ovary cells by a post-transcriptional process, inhibiting translation without affecting either transcription or enzyme degradation (Trzaskos et al., 1993, J. Biol. Chem. 268, 22591-22599). In contrast to the results obtained with the 15alpha-fluorolanostenol, the lanostenol 32-aldehyde increased the rate of degradation of HMGR in a manner similar to that reported for oxycholesterols. These data suggest that 15alpha-fluoro-3beta-hydroxy-lanost-7-en-32-aldehyde and 3beta-hydroxy-lanost-8-en-32-aldehyde, although structurally similar post-transcriptional regulators of HMGR suppress enzyme activity, at least in part, by different mechanisms. (C) 1994 Academic Press, Inc.