Genomic structure and regulation of the rat hepatic CYP4F1 gene by peroxisome proliferators.

The rat hepatic gene CYP4F1 encodes a fatty acid omega hydroxylase P450 that metabolizes proinflammatory eicosanoids and long-chain fatty acids. We have completely sequenced the CYP4F1 gene (Accession Nos. AF200361 and AF181083), identified multiple transcription start sites, and characterized a strong core promoter region, -760/116, induced by retinoic acids and peroxisome proliferators in rat hepatoma McA-RH7777 cells. Three peroxisome proliferator responsive elements (PPRE) bind both PPARalpha/RXRalpha and HNF4alpha. Co-transfection of McA-RH7777 cells with the -760/116 reporter construct and PPARalpha/RXRalpha or HNF4alpha showed that HNF4alpha activated while PPARalpha/RXRalpha inhibited CYP4F1 promoter activity. Treating cells with Wy14,643 reversed all initial effects, indicating co-regulation of CYP4F1 gene transcription by PPARalpha/RXRalpha and HNF4alpha. Chromatin immunoprecipitation analysis of cells treated with Wy14,643 showed association of PPARalpha/RXRalpha with the active transcription of the CYP4F1 gene while in clofibrate treated rats HNF4alpha binds during gene repression, suggesting differential regulation of the CYP4F1 gene in vivo and in cell lines.