THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AT THE CROSS-ROAD OF DIET AND HORMONAL SIGNALING

The peroxisome proliferator-activated receptors (PPARs) are members of the steroid/thyroid nuclear receptor superfamily of ligand-activated transcription factors. To date, three isotypes have been identified, a lpha, beta and gamma, encoded by three different genes. The alpha isot ype is expressed at high levels in the liver where it has a role in li pid oxidation. Its expression and activity follow a diurnal rhythm tha t parallels the circulating levels of corticosterone in the bloodstrea m. The gamma isotype on the other hand, is mainly expressed in adipose tissue and has a critical role in adipocyte differentiation and lipid storage. The function of the ubiquitously expressed isotype, PPAR bet a, remains to be determined. Besides fulfilling different roles in lip id metabolism, the different PPAR isotypes also have different Ligand specificities. A new approach to identify ligands was developed based on the ligand-dependent interaction of PPAR with the recently characte rized co-activator SRC-1. This so-called CARLA assay has allowed the i dentification of fatty acids and eicosanoids as PPAR ligands. Although the evidence clearly links PPAR isotypes to distinct functions, the m olecular basis for this isotype-specificity is still unclear. All thre e isotypes are able to bind the same consensus response element, forme d by a direct repeat of two AGGTCA hexamers separated by one base, tho ugh with different affinities. We recently demonstrated that besides t he core DR-I element, the 5' flanking sequence should be included in t he definition of a PPRE. Interestingly, the presence of this flanking sequence is of particular importance in the context of PPAR alpha bind ing. Moreover, it reflects the polarity of the PPAR-RXR heterodimer on DNA, with PPAR binding to the 5' half-site and RXR binding to the 3' half-site. This unusual polarity may confer unique properties to the b ound heterodimer with respect to Ligand binding and interaction with c o-activators and corepressors. (C) 1998 Elsevier Science Ltd. All righ ts reserved.