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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.