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Repression of CYP4F1 gene by peroxisome proliferators is mediated by HNF4α and PPARα competition for PPRE sites in the CYP4F1 promoter
Author(s) -
Zhang Xiaolan,
Donelson Ellen,
Goswami Puga,
Song Byoung J,
Hardwick James Paul
Publication year - 2006
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.20.4.a460-a
Subject(s) - psychological repression , microbiology and biotechnology , hepatocyte nuclear factor 4 , promoter , transfection , peroxisome proliferator activated receptor , messenger rna , chemistry , gene expression , transcription factor , gene , biology , nuclear receptor , biochemistry
The CYP4F1 P450 catalyzes the hydroxylation of fatty acids and eicosanoids. Unlike the CYP4A1 gene that is induced by peroxisome proliferators (PP), the CYP4F1 gene is repressed in vivo. To determine the mechanism responsible for suppression, we have sequenced the CYP4F1 gene, and identified PPAR∀ and HNF4∀ binding sites in the promoter. In McARH7777 cells treated with PP, 4F1 promoter activity, and mRNA are induced similar to the induction of 4A1 mRNA. In PP treated cells transfected with PPAR∀/RXR∀ or HNF4∀ there is an increase or decrease respectively in promoter activity and 4F1 mRNA. In McARH7777 cells the amount of HNF4∀ protein is less than that found in vivo in the rat liver. Co‐immunoprecipitation analysis indicated an interaction between PPAR∀ and HNF4∀. Cells transfected with HNF4∀ and PPAR∀ showed decreased 4F1 promoter activity and mRNA, which was further decreased with PP. Chip analysis indicated the absence of HNF4∀ binding to the CYP4F1 promoter, but a strong interaction of PPAR∀ with the promoter in cells treated with PP. In cells co‐transfected with HNF4∀ and treated with PP, there is a strong interaction of HNF4∀ with the CYP4F1 promoter, which is similar to that observed in the liver of rats treated with PP. Therefore, CYP4F1 gene repression by PP is mediated by HNF4∀ displacement of PPAR∀ from PPRE sites in the CYP4F1 promoter. This research is supported by Research challenge grant from Ohio Board of Regents.