TitleEvidence against the peroxisome proliferator-activated receptor alpha (PPARalpha) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription.
Publication TypeJournal Article
Year of Publication2000
AuthorsPan, DA, Mater, MK, Thelen, AP, Peters, JM, Gonzalez, FJ, Jump, DB
JournalJ Lipid Res
Date Published2000 May
KeywordsAnimals, Base Sequence, Binding Sites, Clofibrate, Cytochrome P-450 CYP4A, Cytochrome P-450 Enzyme System, Dietary Fats, Unsaturated, DNA Primers, Fatty Acids, Unsaturated, Fish Oils, Humans, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mixed Function Oxygenases, Peroxisome Proliferators, Promoter Regions, Genetic, Pyrimidines, Pyruvate Kinase, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, RNA, Messenger, Transcription Factors, Transcription, Genetic

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 (PPARalpha), binds DR1-like elements and has been reported to interfere with HNF4 action, we examined the role PPARalpha plays in the regulation of L-PK gene transcription. Feeding rats either fish oil or the potent PPARalpha activator, WY14,643, suppressed rat hepatic L-PK mRNA and gene transcription. The PPARalpha-null mouse was used to evaluate the role of the PPARalpha in hepatic transcriptional control of L-PK. While WY14,643 control of L-PK gene expression required the PPARalpha, PUFA regulation of L-PK gene expression was independent of the PPARalpha. Transfection studies in cultured primary hepatocytes localized the cis-regulatory target for WY14,643/PPARalpha action to the L-PK HNF4 binding site. However, PPARalpha/RXRalpha 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 PPARalpha and PPARalpha/RXRalpha does not bind the L-PK promoter. These studies suggest that other intermediary factors are involved in both the PUFA and PPARalpha regulation of L-PK gene transcription.

Alternate JournalJ. Lipid Res.
PubMed ID10787435
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
DK-43220 / DK / NIDDK NIH HHS / United States