THE HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) SUBTYPE NUC1 REPRESSES THE ACTIVATION OF HPPAR-ALPHA AND THYROID-HORMONE RECEPTORS

We have cloned two human peroxisome proliferator-activated receptor (PPAR) subtypes, hPPAR alpha and hNUC1. hPPAR alpha is activated by clofibric acid and other PPAR activators. hNUC1 is not activated by these compounds acting instead as a repressor of hPPAR alpha: and human thyroid hormone receptor transcriptional activation. Repression is specific since hNUC1 does not significantly repress activation by the progesterone or retinoic acid receptors. We demonstrate co-operative binding of hNUC1 and hRXR alpha to a PPAR-responsive element and show that in the presence of hRXR alpha, the affinity of hNUC1 for the peroxisome proliferator is comparable to that of hPPAR alpha. Furthermore, repression of hPPAR alpha can be overcome by transfecting excess hPPAR alpha. We propose that hNUC1 represses the activity of hPPAR alpha by titrating out a factor required for activation. Our data further suggests convergence of thyroid hormone- and peroxisome-mediated fatty acid metabolism pathways. Overcoming hNUC1 repression could be a means of increasing the activity of these receptors.