We have previously demonstrated that dexamethasone (DEX) enhances the T3-dependent increase in type I 5'-deiodinase (5'DI) mRNA in primary cultured rat hepatocytes grown as spheroids. Here we report that DEX-enhanced T3-responsiveness also occurs in two other T3-regulated hepatic genes, Spot 14 and malic enzyme. This enhancement was inhibited by pretreatment with cycloheximide and the stability of 5'DI and Spot 14 mRNAs was not affected by DEX. We thus hypothesized that a factor(s) that augments T3-responsiveness is induced by DEX. Among the possible candidates examined, retinoid-X receptor alpha (RXRalpha), which is a main heterodimer partner with T3 receptor, appeared to be involved. Whereas DEX increased the amount of RXRalpha mRNA, it did not affect the expression of other possible factors such as steroid receptor coactivator-1 and the binding protein of cAMP response element-binding protein. Northern and Western blot analysis, and electrophoretic mobility shift assay revealed that DEX increased RXRalpha expression at both the mRNA and protein levels. Maximal increase in RXRalpha protein was achieved with the addition of physiological concentrations of DEX (10(-8) M). To test whether the DEX-induced increase in RXRalpha affects ligand-dependent transcriptional activation through other receptors that form heterodimer with RXR, we examined its effect on the retinoic acid (RA)/RA receptor (RAR) system. Indeed, DEX also enhanced the RA-dependent increase in RARbeta mRNA in a cycloheximide-sensitive manner. Increase in the level of RXRalpha in hepatocytes by infection with the RXRalpha-expressing adenovirus resulted in enhancement of the T3-dependent increase in 5'DI mRNA. These results strongly suggest that the DEX-induced augmentation of T3-responsiveness in cultured hepatocytes is mediated, in part, by the increased expression of RXRalpha.

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