Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA in rat liver. Glucocorticoids block the stabilization caused by thyroid hormones.
Administration of dexamethasone to hypophysectomized rats treated with thyroid hormones blocked the increase in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA and enzyme activity which occurred in response to thyroid hormone treatment. The rate of transcription of the rat liver HMG-CoA reductase gene measured by "run-on" assays in isolated nuclei was not diminished by dexamethasone. The half-life of HMG-CoA reductase mRNA was decreased from 12-15 to 2-3 h by dexamethasone treatment of hypophysectomized rats fed thyroid powder. Adrenalectomy caused the half-life of HMG-CoA reductase mRNA to increase from 3 to 10 h, suggesting that endogenous glucocorticoids also regulate reductase mRNA stability. Reductase mRNA levels were increased only 5-fold in thyroidectomized rats fed thyroid powder compared to a 20- to 40-fold increase in similarly treated hypophysectomized rats. In thyroidectomized rats, reductase mRNA had a half-life of only 1.5 h. Thyroid hormone treatment increased this to 4.5 h, significantly less than that of similarly treated hypophysectomized rats. Hydrocortisone, like dexamethasone, lowered reductase mRNA levels, but the biologically inactive analogue epihydrocortisone did not affect reductase mRNA or activity. These results suggest that glucocorticoids decrease the abundance of HMG-CoA reductase mRNA by stimulating its degradation.
Simonet
W S
WS
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa 33612.
Ness
G C
GC
D000315:Adrenalectomy; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D006854:Hydrocortisone / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D007016:Hypophysectomy; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010280:Parathyroid Glands / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014020:Tissue Extracts / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D014020:Tissue Extracts; D003907:Dexamethasone; D006903:Hydroxymethylglutaryl CoA Reductases; D006854:Hydrocortisone