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Abstract
The mechanisms by which thyroid hormones and glucocorticoids regulate hepatic HMG-CoA reductase gene expression were investigated in rats. Feeding hypophysectomized rats a diet supplemented with 0.5% desiccated thyroid powder for five days resulted in a 5-fold increase in the rate of transcription of the hepatic HMG-CoA reductase gene. By observing the time course of change in reductase mRNA and approach to new steady state levels of reductase mRNA, it was determined that thyroid hormone treatment also stabilized reductase mRNA 4-6 fold. These two effects appear sufficient to account for the 20 to 40-fold increase in reductase mRNA observed in thyroid hormone treated hypophysectomized rats. Daily injections of dexamethasone given to thyroid hormone treated hypophysectomized rats blocked the increase in reductase mRNA, apparently by destabilizing the mRNA, and without blocking the increase in reductase gene transcription. The half-life of HMG-CoA reductase mRNA was increased from 3 hours in normal rats to 9 hours in adrenalectomized rats. Dexamethasone treatment also destabilized reductase mRNA in adrenalectomized rats. HMG-CoA reductase mRNA was very short lived in thyroidectomized rats (t$\sb{1/2}$ = 1.5 hours), probably due to the normal glucocorticoid levels present in these animals. Feeding thyroidectomized rats a diet supplemented with 0.5% desiccated thyroid powder increased the half-life of reductase mRNA, but not to the extent observed in thyroid hormone treated hypophysectomized rats. Tissue specificity studies indicate that reductase mRNA is increased specifically in the liver of thyroid hormone treated animals, with the possible exception of brain tissue, where a 3 fold increase in reductase mRNA was detected. Little or no increase in reductase mRNA was observed in the small intestine, kidney or heart. Administration of cycloheximide to thyroid hormone treated hypophysectomized rats resulted in a marked decrease in the transcription rate of the hepatic reductase gene and a destabilization of reductase mRNA, but had no effect on $\beta$-actin transcription or steady state levels of $\beta$-actin mRNA. Thus, protein synthesis appears to play an important role in mediating the effects of thyroid hormones on rat liver HMG-CoA reductase mRNA synthesis and degradation.