Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by 24(S),25-oxidolanosterol.
We have examined the mechanism of regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by 24(S),25-oxidolanosterol, a C30-sterol naturally occurring in mammalian tissues. In the absence of enzymatic demethylation to the C27-sterol, 24(S),25-epoxycholesterol, oxidolanosterol is shown to be a post-transcriptional regulator of reductase synthesis in both primary rat hepatocytes and Chinese hamster ovary cells. Under these conditions, oxidolanosterol also increases the rate of degradation of reductase protein in these cells. When demethylation is not inhibited, oxidolanosterol treatment produces transcriptional regulation of sterol-sensitive genes in Chinese hamster ovary cells. In contrast to previous findings with the oxygenated C27-sterol, 25-hydroxycholesterol, oxidolanosterol can act as a post-transcriptional regulator in cells starved for mevalonate. These findings are consistent with the hypothesis that oxidolanosterol down-regulates sterol synthesis in a fashion mechanistically distinct from that of C27-sterols.
Panini
S R
SR
Eleanor Roosevelt Institute, Denver, Colorado 80206.
Delate
T A
TA
Sinensky
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M
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D006224:Cricetinae; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic; D014162:Transfection
D012333:RNA, Messenger; C015410:24,25-oxidolanosterol; D007810:Lanosterol; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D004122:Dimethylallyltranstransferase; D007654:Ketoconazole