CYTOCHROMES P450 .7. ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR IN CYTOCHROME P450-4A GENE-REGULATION

Cytochrome P450s of the 4A subfamily generally catalyze the <(omega)ov er bar>-hydroxylation of fatty acids. The induction of P450 PA enzymes by peroxisome proliferators or fatty acids is mediated by peroxisome proliferator-activated receptors (PPARs), which are members of the nuc lear receptor family that regulates the expression of genes that contr ol fatty acid synthesis, storage, and catabolism. PPARs bind as hetero dimers with another member of the nuclear receptor family, the retinoi d X receptor (RXR), to peroxisome proliferator response elements (PPRE s) in the P450 4A1 and 4A6 genes, PPREs comprise two overlapping motif s for nuclear receptor binding, One motif consists of an imperfect, di rect repeat of two copies of the nuclear receptor core binding site, A GGTCA, separated by a single nucleotide (a DR1 motif) that is recogniz ed by other dimeric nuclear receptor complexes such as HNF-4 or ARP-1. A consensus sequence flanking the DR1 motif together with the 5' core binding site of the DR1 motif constitutes a second, overlapping moth resembling recognition elements for monomeric nuclear receptors, such as Rev-ErbA and the melatonin receptors, PPARs bind to the latter moti f, The tripartite nature of PPREs together with imperfections in the c ore sites of DR1 motif confers specificity for PPAR alpha/RXR alpha bi nding to PPREs relative to other nuclear receptors.