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.
Leonard
D A
DA
Biology Department, West Virginia University, Morgantown 26506-6057.
Kotarski
M A
MA
Tessiatore
J E
JE
Favata
M F
MF
Trzaskos
J M
JM
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis* / Q000235:genetics; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000032:analysis; D058886:Sterol 14-Demethylase
D012333:RNA, Messenger; D007810:Lanosterol; C032444:lanosten-3-ol-32-al; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; D058886:Sterol 14-Demethylase