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PMID:11724780

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Citation

Kawaguchi, T, Osatomi, K, Yamashita, H, Kabashima, T and Uyeda, K (2002) Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J. Biol. Chem. 277:3829-35

Abstract

Carbohydrate-responsive element-binding protein (ChREBP) is a new transcription factor that binds to the carbohydrate-responsive element of the l-type pyruvate kinase gene (l-PK). The aim of this study was to investigate the mechanism by which feeding high fat diets results in decreased activity of ChREBP in the liver (Yamashita, H., Takenoshita, M., Sakurai, M., Bruick, R. K., Henzel, W. J., Shillinglaw, W., Arnot, D., and Uyeda, K. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 9116-9121). We cloned the rat liver ChREBP gene for use throughout this study. Acetate, octanoate, and palmitate inhibited the glucose-induced activation of l-PK transcription in ChREBP-overexpressed hepatocytes. In these hepatocytes, the cytosolic AMP concentration increased 30-fold and AMP-activated protein kinase activity was activated 2-fold. Similarly to the fatty acids, 5-amino-4-imidazolecarboxamide ribotide, a specific activator of AMP-activated protein kinase (AMPK) also inhibited the l-PK transcription activity in ChREBP-overexpressed hepatocytes. Using as a substrate a truncated ChREBP consisting of the C-terminal region, we demonstrated that phosphorylation by AMPK resulted in inactivation of the DNA binding activity. AMPK specifically phosphorylated Ser(568) of ChREBP. A S568A mutant of the ChREBP gene showed tight DNA binding and lost its fatty acid sensitivity, whereas a S568D mutant showed weak DNA binding and inhibited l-PK transcription activity even in the absence of fatty acid. These results strongly suggested that the fatty acid inhibition of glucose-induced l-PK transcription resulted from AMPK phosphorylation of ChREBP at Ser(568), which inactivated the DNA binding activity. AMPK was activated by the increased AMP that was generated by the fatty acid activation.

Links

PubMed Online version:10.1074/jbc.M107895200

Keywords

Amino Acid Sequence; Aminoimidazole Carboxamide/analogs & derivatives; Aminoimidazole Carboxamide/pharmacology; Animals; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cloning, Molecular; Cyclic AMP-Dependent Protein Kinases/metabolism; DNA Primers; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Fatty Acids/metabolism; Glucose/pharmacology; Hepatocytes/metabolism; Humans; Mice; Molecular Sequence Data; Mutagenesis; Pyruvate Kinase/genetics; Rats; Recombinant Proteins/metabolism; Ribonucleotides/pharmacology; Sequence Homology, Amino Acid; Transcription Factors/chemistry; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:AAPK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8VIP2

F

Seeded From UniProt

complete

RAT:AAPK2

involved_in

GO:0097009: energy homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AAPK2

involved_in

GO:0055089: fatty acid homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AAPK2

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:AAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8VIP2

F

Seeded From UniProt

complete

RAT:MLXPL

enables

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MLXPL

involved_in

GO:0097009: energy homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MLXPL

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09137

F

Seeded From UniProt

complete

RAT:MLXPL

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54645

F

Seeded From UniProt

complete

RAT:MLXPL

involved_in

GO:0055089: fatty acid homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MLXPL

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MLXPL

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MLXPL

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MLXPL

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MLXPL

involved_in

GO:0006110: regulation of glycolytic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MLXPL

involved_in

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AAPK1

involved_in

GO:0097009: energy homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AAPK1

involved_in

GO:0055089: fatty acid homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AAPK1

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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