Abstract
Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs. We found that transfecting diabetic rats with TTP did not increase HMGR transcription but rather led to modest inhibition. We then investigated whether co-transfection with protein kinase B, hepatic form (AKT2), might lead to phosphorylation and result in activation of HMGR transcription. We found that this treatment resulted in near complete inhibition of transcription. Transfection with peroxisome proliferator-activated receptor g coactivator (PGC-1a) also inhibited HMGR transcription. These results show that although TTP is needed for activation of HMGR transcription, it cannot by itself activate this process. AKT2 and PGC-1a, which mediate the activation of gluconeogenic genes by insulin, exert the opposite effect on HMGR.
Highlights
The rate of transcription of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is rapidly, within 1 hr increased in response to insulin [1]
Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs
Co-transfection of insulin-treated diabetic rats with TTP resulted in a marked decrease in HMGR promoter activity (Figure 1)
Summary
The rate of transcription of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is rapidly, within 1 hr increased in response to insulin [1]. This leads to correspondingly rapid rises in HMGR mRNA, immunoreactive protein and enzyme activity levels [2,3,4]. One of the characteristics of rapid response genes is the presence of AU-rich sequences in the 3’-untranslated regions of their mRNAs [7] These sequences generally serve as binding sites for proteins that act either to accelerate the rate of degradation of the mRNA or to stabilize it. We have observed a 6-fold increase in TTP protein in liver nuclear extracts from diabetic rats treated with insulin [11]
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