Abstract
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 (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.—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 α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription. J. Lipid Res. 2000. 41: 742–751.
Highlights
The glycolytic enzyme, L-pyruvate kinase (L-PK), plays an important role in hepatic glucose metabolism
cytochrome P450 4A2 (CYP4A2) was used as a positive control for peroxisome proliferator-activated receptor (PPAR)␣ activation [16] while -actin was used to assess the specificity of the treatment effect
Fish oil induced mRNACYP4A2 6.2-fold in the wild-type, but had no significant effect on CYP4A expression in the PPAR␣-null mice. -Actin remained unaffected by these treatments. These results indicate that while the PPAR␣ is required for polyunsaturated fatty acids (PUFA) induction of mRNACYP4A2, it was not required for the PUFA-mediated suppression of mRNALPK
Summary
The glycolytic enzyme, L-pyruvate kinase (L-PK), plays an important role in hepatic glucose metabolism. Because the fatty acid-activated nuclear receptor, peroxisome proliferatoractivated 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. PPAR␣/RXR␣ heterodimers did not bind this region 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. Evidence against the peroxisome proliferator-activated receptor ␣ (PPAR␣) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription.
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