RGD Reference Report - Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. - Rat Genome Database
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Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase.

Authors: Kawaguchi, T  Osatomi, K  Yamashita, H  Kabashima, T  Uyeda, K 
Citation: Kawaguchi T, etal., J Biol Chem 2002 Feb 8;277(6):3829-35.
RGD ID: 634534
Pubmed: (View Article at PubMed) PMID:11724780
DOI: Full-text: DOI:10.1074/jbc.M107895200

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.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component
cytoplasm  (IDA)
nucleus  (IDA)

Molecular Function

Molecular Pathway Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Mlxipl  (MLX interacting protein-like)
Prkaa1  (protein kinase AMP-activated catalytic subunit alpha 1)
Prkaa2  (protein kinase AMP-activated catalytic subunit alpha 2)

Genes (Homo sapiens)
MLXIPL  (MLX interacting protein like)


Additional Information