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

Regulation of human -6 desaturase gene transcription

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

These data indicate that the 5'-flanking region of the human -6 desaturase gene contains a DR-1 that functions in the regulation of human -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 • polyunsaturated fatty acids

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