Post-transcriptional 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 3 beta-hydroxylanost-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 3 beta-hydroxy-lanost-8-en-32-al on HMGR gene expression were examined using a mutant cell line which lacks lanosterol 14 alpha-methyl demethylase activity. Data are presented which suggest that 3 beta-hydroxy-lanost-8-en-32-al inhibits HMGR gene expression by reducing the translational efficiency of the HMGR mRNA. We have recently reported that 15 alpha-fluoro-3 beta-hydroxy-lanost-7-en-32-aldehyde, a compound which is structurally similar to 3 beta-hydroxy-lanost-8-en-32-aldehyde, suppresses HMGR activity in cultured Chinese hamster ovary cells by a posttranscriptional 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 15 alpha-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 15 alpha-fluoro-3 beta-hydroxy-lanost-7-en-32-aldehyde and 3 beta-hydroxy-lanost-8-en-32-aldehyde, although structurally similar posttranscriptional regulators of HMGR suppress enzyme activity, at least in part, by different mechanisms.