DAX-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor HNF4α and Negatively Regulates Gluconeogenic Enzyme Gene Expression

• DOI: 10.1074/jbc.m109.034660
• Publication Date: 2009-08-04T00:59:32Z
• Authors: Balachandar Nedum...; Sungpyo Hong; Yuan-Bin Xie; Yong-Hoon Kim; Woo-Young Seo; Min-Woo Lee; Chul Ho Lee; Seung-Hoi Koo; Hueng-Sik Choi
• Keywords: Blood Glucose; Male; 0301 basic medicine; Base Sequence; DAX-1 Orphan Nuclear Receptor; Gluconeogenesis; Down-Regulation; Dietary Fats; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Gene Expression Regulation, Enzymologic; Cell Line; DNA-Binding Proteins; Mice; 03 medical and health sciences; Hepatocyte Nuclear Factor 4; Liver; Glucose-6-Phosphatase; Hepatocytes; Animals; Humans; Insulin; Insulin Resistance

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.