Transcriptional and posttranscriptional regulation of rat hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by thyroid hormones.
The mechanisms by which thyroid hormones increase hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNA levels were investigated in hypophysectomized rats. Feeding these rats a diet supplemented with 0.5% desiccated porcine thyroid powder resulted in a 5-fold increase in the rate of transcription of the HMG-CoA reductase gene as measured by in vitro "run-on" transcription assays in isolated rat liver nuclei. Time courses of change in reductase mRNA, showing the kinetics of approach to new steady-state levels, indicate that reductase mRNA is also 4-6-fold more stable in thyroid hormone-treated animals than in non-treated animals. Reductase mRNA decayed with a half-life of 2.5 h when mevinolin, a potent inhibitor of HMG-CoA reductase, and colestipol, a bile acid sequesterant, were removed from the diet of hypophysectomized rats. When these drugs were removed from the diet of thyroid hormone-treated hypophysectomized rats, reductase mRNA decayed with a half-life of 15 h. Treating rats with only mevinolin and colestipol increased reductase mRNA levels without stabilizing the mRNA. Administration of cycloheximide to thyroid hormone treated rats rapidly decreased HMG-CoA reductase mRNA levels by destabilizing reductase mRNA and decreasing reductase gene transcription. Cycloheximide treatment had no effect on beta-actin gene transcription or steady state levels of beta-actin mRNA. These results suggest that a short-lived protein(s) may mediate the transcriptional and post-transcriptional effects of thyroid hormones on HMG-CoA reductase mRNA levels.
Simonet
W S
WS
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa 33612.
Ness
G C
GC
D000199:Actins / Q000235:genetics; D000818:Animals; D003084:Colestipol / Q000008:administration & dosage / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004032:Diet; D005786:Gene Expression Regulation / Q000187:drug effects*; D006207:Half-Life; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D007016:Hypophysectomy; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
D000199:Actins; D012333:RNA, Messenger; D013963:Thyroid Hormones; D003513:Cycloheximide; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D003084:Colestipol