Thyromimetic effect of peroxisomal proliferators in rat liver

Amphipathic carboxylates, of varying hydrophobic backbones, which act as peroxisomal proliferators (aryloxyalkanoic acids, methyl-substituted dicarboxylic acid) induce in euthyroid or thyroidectomized rats, as well as in rat hepatocytes cultured in 3,5,3'-tri-iodo-L-thyronine (T₃)-free media, liver enzyme activities that are classically considered to be thyroid-hormone-dependent (malic enzyme, mitochondrial α-glycerophosphate dehydrogenase, glucose-6-phosphate dehydrogenase and S14). The dose required in vivo for the thyromimetic effect of peroxisomal proliferators was 10³-fold higher than the dose of T₃ required. Similarly, peroxisomal proliferators were active in culture in the range 1-100 μM compared with 1 nM for T₃. Their maximal inductive capacities were, however, similar to or greater than that of T₃. The thyromimetic effect of peroxisomal proliferators was only partially correlated with their capacities as inducers of liver peroxisomal enzymes. The thyromimetic effect with respect to liver malate dehydrogenase and S14 resulted from an increase in their mRNA contents. The increase in liver S14 mRNA was accounted for by transcriptional activation of the S14 gene. T₃ binding to isolated liver nuclei or nuclear extract was competitively displaced by some but not all of the nonthyroidal inducers of the above liver activities. In contrast with the thyromimetic effect induced in liver cells, no increase in growth hormone mRNA was observed in cultured GH₁ pituitary cells incubated in the presence of non-thyroidal amphipathic carboxylates. The characteristics of the thyromimetic effect of amphipathic carboxylic peroxisomal proliferators indicate that these agents may act as transcriptional activators of thyroid-hormone-dependent genes in the rat liver.