TitleRegulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-alpha agonist.
Publication TypeJournal Article
Year of Publication2006
AuthorsXu, J, Christian, B, Jump, DB
JournalJ Biol Chem
Date Published2006 Jul 07
KeywordsAnimals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cells, Cultured, Enzyme Induction, Fatty Acids, Unsaturated, Gene Expression Regulation, Enzymologic, Glucose, Hepatocyte Nuclear Factor 4, Hepatocytes, Liver, Male, PPAR alpha, Promoter Regions, Genetic, Pyrimidines, Pyruvate Kinase, Rats, Rats, Sprague-Dawley, Trans-Activators, Transcriptional Activation

Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X (MLX), and hepatic nuclear factor-4alpha (HNF-4alpha) are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferator-activated receptor alpha (PPARalpha) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNA(L-PK) but did not suppress hepatic ChREBP or HNF-4alpha nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNA(LPK) and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4alpha. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4alpha-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4alpha-LPK promoter interaction. Although overexpressed ChREBP or HNF-4alpha did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNA(L-PK) abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA and WY14643/PPARalpha target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation.

Alternate JournalJ Biol Chem
PubMed ID16644726
PubMed Central IDPMC2766394
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
R01 DK043220-14 / DK / NIDDK NIH HHS / United States
DK43220 / DK / NIDDK NIH HHS / United States