Transcriptional regulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver.
This study addresses whether transcriptional control of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver plays a role in determining the level of reductase mRNA. Isolated rat liver nuclei were allowed to elongate nascent RNA transcripts in the presence of [alpha-32P]CTP, and radiolabeled nuclear reductase RNA was quantitated by filter hybridization. Rats fed a diet supplemented with the drugs cholestyramine and mevinolin and having 20-60-fold induced levels of reductase mRNA exhibited levels of reductase transcription which were 20-fold higher than in rats fed an unsupplemented diet. Over 90% of the transcription of the reductase gene was inhibited by concentrations of alpha-amanitin which selectively inhibit RNA polymerase II. Administration of mevalonolactone (the end product of the reaction catalyzed by reductase) to rats fed cholestyramine and mevinolin caused an 80% decrease in the rate of reductase transcription by approximately 1 h. We conclude that under these conditions changes in reductase transcription are primarily responsible for the regulation of reductase mRNA levels.
D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D002792:Cholestyramine Resin / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000201:enzymology*; D008148:Lovastatin; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic
D000546:Amanitins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D012333:RNA, Messenger; D002792:Cholestyramine Resin; C015367:mevalonolactone; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D012319:RNA Polymerase II; D008798:Mevalonic Acid