TitleDietary polyunsaturated fatty acids interfere with the insulin/glucose activation of L-type pyruvate kinase gene transcription.
Publication TypeJournal Article
Year of Publication1994
AuthorsLiimatta, M, Towle, HC, Clarke, S, Jump, DB
JournalMol Endocrinol
Date Published1994 Sep
KeywordsAnimals, Arachidonic Acid, Base Sequence, Cells, Cultured, Depression, Chemical, Dietary Fats, DNA-Binding Proteins, Eicosapentaenoic Acid, Enzyme Induction, Fatty Acids, Unsaturated, Fish Oils, Glucose, Glycolysis, Hepatocyte Nuclear Factor 4, Insulin, Liver, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Oleic Acid, Oleic Acids, Phosphoproteins, Pyruvate Kinase, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic


L-type pyruvate kinase (L-PK) is a key glycolytic enzyme regulating the flux of metabolites through the pyruvate-phosphoenolpyruvate cycle (1). The regulation of L-PK is complex involving both hormones and nutrients. We have found that feeding rats diets containing polyunsaturated fatty acids (PUFA) significantly inhibits hepatic pyruvate kinase enzyme activity (> 60%) and suppresses mRNAPK abundance (> 70%). Studies with primary hepatocytes indicate that PUFA act directly on hepatocytes. Specifically, arachidonic (20:4, omega 6) and eicosapentaenoic (20:5, omega 3) acid suppressed both mRNAPK llevels and the activity of a transfected PKCAT (-4300/+12) fusion gene by > 70%. This is due to an inhibition of the insulin/glucose-mediated transactivation of L-PKCAT. Deletion analysis localized PUFA-regulated cis-acting elements to a region within the L-PK proximal promoter, i.e. between -197 and -96 base pairs. This region binds two transcription factors involved in the hormone/nutrient regulation of L-PK gene transcription, i.e. a major late transcription factor-like factor and HNF-4. Linker scanning mutation analysis localized the PUFA-regulated cis-acting elements to the vicinity of the HNF-4 binding site. Thus, PUFA-regulated factors abrogate the insulin/glucose activation of L-PK gene transcription by targeting the HNF-4 elements. These studies suggest that PUFA may have significant effects on hepatic carbohydrate metabolism by inhibiting the L-PK side of the pyruvate-phosphoenolpyruvate cycle.

Alternate JournalMol. Endocrinol.
PubMed ID7838147
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
DK-26919 / DK / NIDDK NIH HHS / United States
DK-43220 / DK / NIDDK NIH HHS / United States