Crosstalk between the thyroid hormone and peroxisome proliferator-activated receptors in regulating peroxisome proliferator-responsive genes

Abstract

Peroxisome proliferators and thyroid hormones have overlapping metabolic effects and regulate a similar subset of genes involved in maintaining lipid homeostasis. Transcriptional activation by peroxisome proliferators is mediated by peroxisome proliferator-activated receptors (PPARs) that bind to specific peroxisome proliferator-response elements (PPREs) through heterodimerization with retinoid X receptors (RXRs). We examined the effect of thyroid hormone receptor α (TRα) on DNA binding in vitro and transcriptional activation in vivo by rat PPAR. Gel mobility shift assays using in vitro translated receptors demonstrated that TRα was capable of binding on its own and cooperatively with RXRα to the rat acyl-CoA oxidase PPRE and of inhibiting the binding of rat PPAR RXRα heterodimers to this element. This inhibition was the result of competition between TRα and PPAR for limiting amounts of the heterodimerization partner RXRα and for binding to the PPRE. Interestingly, cotransfection of a TRα expression plasmid into mammalian cells resulted in potentiation of the peroxisome proliferator- and PPAR RXRα - dependent transcriptional induction of a reporter gene containing the acyl-CoA oxidase PPRE. TRα therefore appears to cooperate with RXR and PPAR to positively modulate peroxisome proliferator-dependent transactivation in vivo. Our findings suggest that there is crosstalk between the thyroid hormone and peroxisome proliferator signaling pathways in the regulation of peroxisome proliferator-responsive genes.