Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription
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...
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doaj-1a16505d17984b7b80355359583591762021-04-27T04:42:31ZengElsevierJournal of Lipid Research0022-22752000-05-01415742751Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcriptionDavid A. Pan0Michelle K. Mater1Annette P. Thelen2Jeffrey M. Peters3Frank J. Gonzalez4Donald B. Jump5Departments of Physiology, Biochemistry, Botany, and Plant Pathology, Michigan State University, East Lansing, MI 48824Departments of Physiology, Biochemistry, Botany, and Plant Pathology, Michigan State University, East Lansing, MI 48824Departments of Physiology, Biochemistry, Botany, and Plant Pathology, Michigan State University, East Lansing, MI 48824Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892To whom correspondence should be addressed.; Departments of Physiology, Biochemistry, Botany, and Plant Pathology, Michigan State University, East Lansing, MI 48824The 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.http://www.sciencedirect.com/science/article/pii/S002222752032383XHepatic nuclear factor-4 (HNF4)peroxisome proliferatorscytochrome P450 4Aglycolysislipogenesis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David A. Pan Michelle K. Mater Annette P. Thelen Jeffrey M. Peters Frank J. Gonzalez Donald B. Jump |
spellingShingle |
David A. Pan Michelle K. Mater Annette P. Thelen Jeffrey M. Peters Frank J. Gonzalez Donald 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 Journal of Lipid Research Hepatic nuclear factor-4 (HNF4) peroxisome proliferators cytochrome P450 4A glycolysis lipogenesis |
author_facet |
David A. Pan Michelle K. Mater Annette P. Thelen Jeffrey M. Peters Frank J. Gonzalez Donald B. Jump |
author_sort |
David A. Pan |
title |
Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription |
title_short |
Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription |
title_full |
Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription |
title_fullStr |
Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription |
title_full_unstemmed |
Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription |
title_sort |
evidence against the peroxisome proliferator-activated receptor α (pparα) as the mediator for polyunsaturated fatty acid suppression of hepatic l-pyruvate kinase gene transcription |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2000-05-01 |
description |
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. |
topic |
Hepatic nuclear factor-4 (HNF4) peroxisome proliferators cytochrome P450 4A glycolysis lipogenesis |
url |
http://www.sciencedirect.com/science/article/pii/S002222752032383X |
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