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 add-activated nuclear receptor, peroxisome proliferator-activated receptor (PPARα), binds DR1-like elements and has been reported to interfere with HNF4 action, we examined the role PPARα plays in the regulation of L-PK gene transcription. Feeding rats either fish oil or the potent PPARα activator, WY14,643, suppressed rat hepatic L-PK mRNA and gene transcription. The PPARα-null mouse was used to evaluate the role of the PPARα in hepatic transcriptional control of L-PK. While WY14,643 control of L-PK gene expression required the PPARα, PUFA regulation of L-PK gene expression was independent of the PPARα. Transfection studies in cultured primary hepatocytes localized the cis-regulatory target for WY14,643/PPARα action to the L-PK HNF4 binding site. However, PPARα/RXRα 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 PPARα and PPARα/RXRα does not bind the L-PK promoter. These studies suggest that other intermediary factors are involved in both the PUFA and PPARα regulation of L-PK gene transcription.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Lipid Research|
|State||Published - May 2000|
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