trichostatin-a and darglitazone

The stimulation of the uncoupling protein-2 gene (ucp2) by thyroid hormone (triiodothyronine [T3]) in vivo is variable, suggesting complex interactions and even the possibility of indirect effects. We investigated the effect of T3 on ucp2 expression in L6 myotubules. Alone, T3 did not significantly stimulate ucp2 expression in L6 cells, but it amplified the stimulation by thiazolidinediones (TZDs). L6 cells expressed both alpha1 and beta1 thyroid hormone receptors and the data were consistent with the effect being mediated by these receptors. T3 also enhanced the stimulation of ucp2 by the nonselective peroxisome proliferator-activated receptor (PPAR) ligands bezafibrate and carbacyclin, but not that by oleic acid or norepinephrine. L6 cells expressed PPARbeta and PPARgamma, but not PPARalpha. As short as a 1-h preexposure of L6 cells to T3 was sufficient to amplify the effect of PPAR ligands. Neither transcription nor translation was needed for this effect of T3. T3 did not affect the t1/2 of UCP2 mRNA. The histone deacetylases inhibitor trichostatin A (TSA) stimulated the expression of ucp2 but did not add to the effect of T3 nor did this hormone enhance the effect of TSA. These results suggest that T3 selectively enhances the transcriptional stimulation of ucp2 by TZDs and nonselective PPAR ligands by priming the gene to a transactivating signal(s) generated by such ligands.

Topics: Amanitins; Animals; Cell Line; Drug Synergism; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Hydroxamic Acids; Ion Channels; Membrane Transport Proteins; Mitochondrial Proteins; Molecular Sequence Data; Muscle Fibers, Skeletal; Muscle, Skeletal; Nucleic Acid Synthesis Inhibitors; Osmolar Concentration; Protein Biosynthesis; Proteins; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Thyroid Hormone; RNA, Messenger; Stereoisomerism; Thiazoles; Thiazolidinediones; Thyroxine; Transcription Factors; Transcription, Genetic; Triiodothyronine; Uncoupling Protein 2