DAX-1 acts as a novel corepressor of orphan nuclear receptor HNF4α and negatively regulates gluconeogenic enzyme gene expression

Balachandar Nedumaran, Sungpyo Hong, Yuan Bin Xie, Yong Hoon Kim, Woo Young Seo, Min Woo Lee, Chul Ho Lee, Seung Hoi Koo, Hueng Sik Choi

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32 Citations (Scopus)

Abstract

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. HNF4α (hepatocyte nuclear factor 4α) 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 ofHNF4α 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 HNF4α 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-1α and HNF4α under fasting and refeeding, showing that DAX-1 could compete with the coactivator PGC-1α for binding to HNF4α. Adenovirus-mediated expression of DAX-1 decreased both HNF4α- 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 HNF4α to negatively regulate hepatic gluconeogenic gene expression in liver.

Original languageEnglish
Pages (from-to)27511-27523
Number of pages13
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
Publication statusPublished - 2009 Oct 2

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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