Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation.
Cytochrome P450s of the 4A subfamily generally catalyze the omega-hydroxylation of fatty acids. The induction of P450 4A enzymes by peroxisome proliferators or fatty acids is mediated by peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear receptor family that regulates the expression of genes that control fatty acid synthesis, storage, and catabolism. PPARs bind as heterodimers with another member of the nuclear receptor family, the retinoid X receptor (RXR), to peroxisome proliferator response elements (PPREs) in the P450 4A1 and 4A6 genes. PPREs comprise two overlapping motifs for nuclear receptor binding. One motif consists of an imperfect, direct repeat of two copies of the nuclear receptor core binding site, AGGTCA, separated by a single nucleotide (a DR1 motif) that is recognized 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 motif resembling recognition elements for monomeric nuclear receptors, such as Rev-ErbA and the melatonin receptors. PPARs bind to the latter motif. The tripartite nature of PPREs together with imperfections in the core sites of DR1 motif confers specificity for PPAR alpha/RXR alpha binding to PPREs relative to other nuclear receptors.
Johnson
E F
EF
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, USA.
Palmer
C N
CN
Griffin
K J
KJ
Hsu
M H
MH
D000818:Animals; D001483:Base Sequence; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A