Post-transcriptional Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase by 3β-Hydroxy-Lanost-8-en-32-Al, an Intermediate in the Conversion of Lanosterol to Cholesterol

Abstract The lanosterol demethylation intermediate 3β-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 3β-hydroxy-lanost-8-en-32-al on HMGR gene expression were examined using a mutant cell line which lacks lanosterol 14α-methyl demethylase activity. Data are presented which suggest that 3β-hydroxy-lanost-8-en-32-al inhibits HMGR gene expression by reducing the translational efficiency of the HMGR mRNA. We have recently reported that 15α-fluoro-3β-hydroxy-lanost-7-en-32-aldehyde, a compound which is structurally similar to 3β-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 15α-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 15α-fluoro-3β-hydroxy-lanost-7-en-32-aldehyde and 3β-hydroxy-lanost-8-en-32-aldehyde, although structurally similar post-transcriptional regulators of HMGR suppress enzyme activity, at least in part, by different mechanisms.