THYROMIMETIC EFFECT OF PEROXISOME PROLIFERATORS

Xenobiotic amphipathic carboxylates of varying hydrophobic backbones, known collectively as 'peroxisome proliferators' (PP), affect lipoprotein metabolism, calorigenesis, liver redox and phosphate potentials and adipose conversion. Some biological effects exerted by PP are strikingly similar to those exerted by thyroid hormones (TH). Furthermore, similarly to TH, these compounds have been recently found to induce in euthyroid as well as thyroidectomized rats or in rat hepatocytes cultured in TH-free media, liver activities classically considered as TH-dependent, eg malic enzyme (ME) and S14. The thyromimetic effect of PP could be accounted for by transcriptional activation of TH-dependent genes as verified by run-on transcription assays. The thyromimetic effect of PP was found not to be mediated by the TH nuclear receptor. Moreover, in contrast to TH, PP were ineffective as thyromimetic agents in the rat heart or pituitary cells, suggesting a tissue specificity different from that of TH. The overall thyromimetic effect of PP appears to involve transcriptional activation of TH-dependent genes, yet being mediated.by a novel transduction pathway.