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Papers In Press, published online ahead of print January 16, 2003
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Pennington Biomedical Research Center, Baton Rouge, LA 70808
Corresponding Author: ClarkeSD{at}pbrc.edu
Arachidonic [20:4(n-6)] and docosahexenoic [22:6(n-3)] acids are potent inhibitors of lipogenic gene expression and consequently reduce the hepatic secretion and tissue accumulation of triglycerides. The rate-limiting step in 20:4(n-6) and 22:6(n-3) synthesis is the desaturation of 18:2(n-6) and 18:3(n-3) by delta-6 desaturase (D6ase). In this report, we demonstrate that (n-6) and (n-3) polyunsaturated fats (PUFA) suppressed the hepatic expression of rodent D6ase by inhibiting the rate of D6ase gene transcription. In contrast, consumption of the PPARa activator WY 14,643 significantly enhanced the transcription of hepatic D6ase by more than 500%. Transfection-reporter assays with HepG2 cells revealed that the PUFA response region for the human D6ase gene involved the proximal promoter region of –283/+1 human D6ase gene, while the WY 14,643 response element was identified as an imperfect direct repeat (DR-1) located at –385/-373. The WY 14,643 induction of the human D6ase promoter activity was dependent upon the expression of PPARa. Electrophoretic mobility shift assays revealed that nuclear proteins extracted from HepG2 cells expressing PPARa specifically interacted with the –385/-373 DR-1 sequence of the human D6ase gene. The interaction was eliminated by unlabelled PPARa-response element of the rat acyl-CoA oxidase gene, and the protein/DNA complex was super-shifted by treatment with anti-PPARa. The –385/-373 sequence also interacted with a mixture of in vitro translated PPARa/RXRa but by themselves neither PPARa nor RXRa could bind to the D6ase DR-1. These data indicate that the 5’-flanking region of the human D6ase gene contains a DR-1 that functions in the regulation of human D6ase gene transcription, and thereby plays a role in the synthesis of 20- and 22-carbon polyenoic fatty acids.
Revised on January 2, 2003
Accepted on January 3, 2003
Transcriptional regulation of rat and human delta-6 desaturase genes by fatty acids and WY 14,643: Identification of a functional direct repeat-1 cis-acting element in the human delta-6 desaturase gene
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