Regulation of the action of steroid-thyroid hormone receptors by medium-chain fatty acids

Triiodothyronine (T 3 ) causes a 30-fold increase in transcription of the malic enzyme gene in chick embryo hepatocytes; medium-chain fatty acids (MCFAs) inhibit this increase. T 3 action is mediated by T 3 receptors (TRs) that bind to T 3 response elements (T 3 REs) in this gene’s 5′-flanking DNA. In transiently transfected hepatocytes, fragments of 5′-flanking DNA of the malic enzyme gene or artificial T 3 REs that conferred T 3 stimulation also conferred MCFA inhibition to linked reporter genes. Thus, MCFA inhibition may be mediated through cis-acting T 3 REs and trans-acting TRs, distinguishing MCFA action from that of other fatty acids which act through unique sequence elements. Using binding assays and overexpression of TR, we showed that MCFAs inhibited the transactivating but not the silencing function of TR and did not alter binding of T 3 to TR or of TR to T 3 RE. The C-terminal ligand-binding domain of TR was sufficient to confer stimulation by T 3, but not inhibition by MCFA. Inhibition of transactivation by MCFA was specific: ligand-stimulated transcription from T 3 or estrogen response elements was inhibited, but that from glucocorticoid or cyclic AMP response elements was not. We propose that MCFAs or metabolites thereof influence the activity of a factor(s) that interacts with the T 3 and estrogen receptors to inhibit ligand-stimulated transcription.