Regulation of P450 4A expression by peroxisome proliferator activated receptors

The induction of P450 4A enzymes by peroxisome proliferators (PPs) and fatty acids is mediated by the peroxisome proliferator activated receptor alpha (PPAR alpha) that binds to response elements in target genes as a heterodimer with the retinoid X receptor (RXR). The consensus sequence recognized by PPAR/RXR heterodimers, contains an imperfect direct repeat of two nuclear receptor binding motifs separated by a single nucleotide. This repeat is preceded by a conserved A/T rich sequence that is required for function. In mice, chronic exposure to PPs results in PPAR alpha mediated liver hypertrophy, hyperplasia and carcinogenesis accompanied by a proliferation of peroxisomes. In contrast, humans exhibit a reduced sensitivity to PP pathogenesis. This could reflect >10-fold lower PPAR alpha levels relative to mice as well as differences in targeted genes. In order to identify PPAR responsive human genes, the human hepatoma cell line, HepG2, was engineered to express increased levels of PPAR alpha. Several genes encoding rate-limiting enzymes and branch points in ketone body formation are regulated by PPAR alpha in these cells. In contrast, significant induction by PP is not evident for peroxisomal fatty acid oxidation that is associated with peroxisome proliferation in mice. Human P450 4A11 is not expressed in dividing cultures of cells with enhanced PPAR alpha levels, but it is expressed in confluent cultures expressing elevated amounts of PPAR alpha.