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Role of the peroxisome proliferator‐activated receptor in cytochrome P450 4A gene regulation
Author(s) -
Johnson Eric F.,
Palmer Colin N. A.,
Griffin Keith J.,
Hsu MeiHui
Publication year - 1996
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.10.11.8836037
Subject(s) - nuclear receptor , retinoid x receptor , peroxisome proliferator activated receptor alpha , peroxisome proliferator activated receptor , biology , receptor , biochemistry , sequence motif , cytochrome p450 , transcription factor , gene , enzyme
Cytochrome P450s of the 4A subfamily generally catalyze the ω‐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 PPARα/RXRα binding to PPREs relative to other nuclear receptors.—Johnson, E. F., Palmer, C. N. A., Griffin, K. J., Hsu, M.‐H. Role of the peroxisome proliferator‐activated receptor in cytochrome P450 4A gene regulation. FASEB J. 10, 1241‐1248 (1996)