Original Article

Evidence against the peroxisome proliferator-activated receptor (PPAR) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription

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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