DAX-1 acts as a novel corepressor of orphan nuclear receptor HNF4alpha and negatively regulates gluconeogenic enzyme gene expression.
DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family and acts as a corepressor of a number of nuclear receptors. HNF4alpha (hepatocyte nuclear factor 4alpha) is a liver-enriched transcription factor that controls the expression of a ... variety of genes involved in cholesterol, fatty acid, and glucose metabolism. Here we show that DAX-1 inhibits transcriptional activity of HNF4alpha and modulates hepatic gluconeogenic gene expression. Hepatic DAX-1 expression is increased by insulin and SIK1 (salt-inducible kinase 1), whereas it is decreased in high fat diet-fed and diabetic mice. Coimmunoprecipitation assay from mouse liver samples depicts that endogenous DAX-1 interacts with HNF4alpha in vivo. In vivo chromatin immunoprecipitation assay affirms that the recruitment of DAX-1 on the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter is inversely correlated with the recruitment of PGC-1alpha and HNF4alpha under fasting and refeeding, showing that DAX-1 could compete with the coactivator PGC-1alpha for binding to HNF4alpha. Adenovirus-mediated expression of DAX-1 decreased both HNF4alpha- and forskolin-mediated gluconeogenic gene expressions. In addition, knockdown of DAX-1 partially reverses the insulin-mediated inhibition of gluconeogenic gene expression in primary hepatocytes. Finally, DAX-1 inhibits PEPCK and glucose-6-phosphatase gene expression and significantly lowers fasting blood glucose level in high fat diet-fed mice, suggesting that DAX-1 can modulate hepatic gluconeogenesis in vivo. Overall, this study demonstrates that DAX-1 acts as a corepressor of HNF4alpha to negatively regulate hepatic gluconeogenic gene expression in liver.
Mesh Terms:
Animals, Base Sequence, Blood Glucose, Cell Line, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Dietary Fats, Down-Regulation, Gene Expression Regulation, Enzymologic, Gluconeogenesis, Glucose-6-Phosphatase, Hepatocyte Nuclear Factor 4, Hepatocytes, Humans, Insulin, Insulin Resistance, Liver, Male, Mice, Phosphotransferases, Protein Structure, Tertiary, Protein Transport, Rats, Receptors, Retinoic Acid, Repressor Proteins, Trans-Activators, Transcription, Genetic, Transcriptional Activation
Animals, Base Sequence, Blood Glucose, Cell Line, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Dietary Fats, Down-Regulation, Gene Expression Regulation, Enzymologic, Gluconeogenesis, Glucose-6-Phosphatase, Hepatocyte Nuclear Factor 4, Hepatocytes, Humans, Insulin, Insulin Resistance, Liver, Male, Mice, Phosphotransferases, Protein Structure, Tertiary, Protein Transport, Rats, Receptors, Retinoic Acid, Repressor Proteins, Trans-Activators, Transcription, Genetic, Transcriptional Activation
J. Biol. Chem.
Date: Oct. 02, 2009
PubMed ID: 19651776
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