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Journal of Lipid Research, Vol. 41, 742-751, May 2000
Copyright © 2000 by Lipid Research, Inc.
Evidence against the peroxisome proliferator-activated receptor (PPAR ) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription
David A. Pana,
Michelle K. Matera,
Annette P. Thelena,
Jeffrey M. Petersb,
Frank J. Gonzalezb, and
Donald B. Jumpa
a Departments of Physiology, Biochemistry, Botany, and Plant Pathology, Michigan State University, East Lansing, MI 48824
b Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Correspondence to:
Donald B. Jump
The glycolytic enzyme, L-pyruvate kinase (L-PK), plays an important role in hepatic glucose metabolism. Insulin and glucose induce L-PK gene expression, while glucagon and polyunsaturated fatty acids (PUFA) inhibit L-PK gene expression. We have been interested in defining the PUFA regulation of L-PK. The cis-regulatory target for PUFA action includes an imperfect direct repeat (DR1) that binds HNF-4. HNF4 plays an ancillary role in the insulin/glucose-mediated transactivation of the L-PK gene. Because the fatty acid-activated nuclear receptor, peroxisome proliferator-activated receptor (PPAR ), binds DR1-like elements and has been reported to interfere with HNF4 action, we examined the role PPAR plays in the regulation of L-PK gene transcription. Feeding rats either fish oil or the potent PPAR activator, WY14,643, suppressed rat hepatic L-PK mRNA and gene transcription. The PPAR -null mouse was used to evaluate the role of the PPAR in hepatic transcriptional control of L-PK. While WY14,643 control of L-PK gene expression required the PPAR , PUFA regulation of L-PK gene expression was independent of the PPAR . Transfection studies in cultured primary hepatocytes localized the cis-regulatory target for WY14,643/PPAR action to the L-PK HNF4 binding site. However, PPAR /RXR heterodimers did not bind this region. Although both WY14,643 and PUFA suppress L-PK gene transcription through the same element, PUFA regulation of L-PK does not require the PPAR and PPAR /RXR does not bind the L-PK promoter.
These studies suggest that other intermediary factors are involved in both the PUFA and PPAR regulation of L-PK gene transcription.Pan, D. A., M. K. Mater, A. P. Thelen, J. M. Peters, F. J. Gonzalez, and D. B. Jump. Evidence against the peroxisome proliferator-activated receptor (PPAR ) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription. J. Lipid Res. 2000. 41: 742;751.
Supplementary key words:
Hepatic nuclear factor-4 (HNF4), peroxisome proliferators, cytochrome P450 4A, glycolysis, lipogenesis

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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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