B. Desvergne et al., THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AT THE CROSS-ROAD OF DIET AND HORMONAL SIGNALING, Journal of steroid biochemistry and molecular biology, 65(1-6), 1998, pp. 65-74
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.