ABSTRACT
Peroxisomal proliferator-activated receptor (PPAR) is a member of the nuclear rei::eptor superfamily that is activated in response to a variety of amphipathic carboxylates, including herbicides, industrial plasticizers, and hypolipidemic
such as clofibrk acid ( 45). In rodents, these molecules result in dramatic increases in the size and number of peroxisomes in the liver and kidney and hence are termed peroxisome proliferators (46). Recently, an HRE was identified in the promoter of the acyl-CoA oxidase gene that confers responsiveness to peroxisome proliferators (Figure 4) (47-49); this peroxisomal proliferator response element
is an imperfect DR-1 motif. The in structures of this PPRE with previously defined RXREs together with the observation that oxidase gene expression in hepatocytes is activated in response to both peroxisome proliferators and RA (50) suggested the possibility of a PPAR-RXR heterodimeric interaction. Indeed, in vitro studies revealed that RXR and PP AR form a heterodimer in solution which selectively binds DR-1-like HREs, includ-
the acyl-CoA oxidase PPRE (32). As predicted by these in vitro analyses, the PP AR-RXR activated expression of either the intact acyl-CoA oxidase promoter or a heterologous promoter driven by a PPRE in response to either clofibric acid or 9~cis-RA. Interestingly, treatment with both hormones resulted in a synergistic induction of gene expression (32). These data demonstrate the coupling of the 9-cis-RA and peroxisome proliferator signaling pathways through PPAR-RXRa interactions on the DR-1 motif. Furthermore, the results
"'"""''"~" evidence that a nuclear receptor hetemdimer can interact with either alone or both simultaneously, yielding three discrete levels
of activation. Thus, the formation of heterodimers between members of the steroid/thyroid hormone receptor superfamily not only yields complexes with distinct binding site preferences but also results in transcription factors with multiple activation states. The binding specificities and activities of the RXR
.As mentioned, we previously suggested that RXRa. may be involved in the regulation of basic metabolic pathways retinoid metabolism. This proposal was initially based on the abundant expression of RXRa in visceral tissues, including liver and kidney, and was bolstered by the fmdings that the CRBPII (30) and apolipoprotein Al genes ( 44) are responsive to RXR. CRBPH is invollved in the and subsequent chylomicron-mediated transport of
5 Heterodimers formed between RXR other members of the sicomid/thyroid hormone receptor (left) RXR heterodimers with eiiher peroxisome proliferator-activated receptor (PP AR), vitamin D receptor (VDR), thyroid hormone receptor (fR), or retinoic acid receptor (RAR), which positively regulate gene expression through HREs composed of tandem repeats spaced by 1, 3, 4, or 5 nucleotides, respectively. (right) RXR forms heterodimers with COUP-TF and RAR that negatively regulate gene """''""'''"" through HREs composed of tandem n::pe21ts spaced by a single nucleotide.
