J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M200195-JLR200 on January 16, 2003

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Journal of Lipid Research, Vol. 44, 686-695, April 2003
Copyright © 2003 by Lipid Research, Inc.

Regulation of human {Delta}-6 desaturase gene transcription

: identification of a functional direct repeat-1 element

Chongren Tang1, Hyekung P. Cho, Manabu T. Nakamura and Steven D. Clarke2

Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808

2 To whom correspondence should be addressed. e-mail: clarkesd{at}pbrc.edu

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. In this report, we demonstrate that n-6 and n-3 PUFAs suppressed the hepatic expression of rodent {Delta}-6 desaturase by inhibiting the rate of {Delta}-6 desaturase gene transcription. In contrast, consumption of the peroxisome proliferator-activated receptor (PPAR){alpha} activator WY 14,643 significantly enhanced the transcription of hepatic {Delta}-6 desaturase by more than 500%. Transfection reporter assays with HepG2 cells revealed that the PUFA response region for the human {Delta}-6 desaturase gene involved the proximal promoter region of -283/+1 human {Delta}-6 desaturase gene, while the WY 14,643 response element (RE) was identified as an imperfect direct repeat (DR-1) located at -385/-373. The WY 14,643 induction of the human {Delta}-6 desaturase promoter activity was dependent upon the expression of PPAR{alpha}. Electrophoretic mobility shift assays revealed that nuclear proteins extracted from HepG2 cells expressing PPAR{alpha} specifically interacted with the -385/-373 DR-1 sequence of the human {Delta}-6 desaturase gene. The interaction was eliminated by the unlabeled PPAR{alpha} RE of the rat acyl-CoA oxidase gene, and the protein-DNA complex was super-shifted by treatment with anti-PPAR{alpha}. The -385/-373 sequence also interacted with a mixture of in vitro translated PPAR{alpha}-retinoic acid receptor X (RXR){alpha}, but by themselves neither PPAR{alpha} nor RXR{alpha} could bind to the {Delta}-6 desaturase DR-1.

These data indicate that the 5'-flanking region of the human {Delta}-6 desaturase gene contains a DR-1 that functions in the regulation of human {Delta}-6 desaturase gene transcription, and thereby plays a role in the synthesis of 20- and 22-carbon polyenoic fatty acids.

Abbreviations: EMSA, electrophoretic mobility shift assay; HNF-4, hepatic nuclear factor 4; nt, nucleotide; PPAR, peroxisome proliferator-activated receptor; RLU, relative light unit; RXR, retinoic acid receptor X; SREBP-1, sterol regulatory element binding protein-1

Supplementary key words liver • peroxisome proliferator-activated receptor {alpha} • polyunsaturated fatty acids


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