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.
Nedumaran
Balachandar
B
Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, South Korea.
Hong
Sungpyo
S
Xie
Yuan-Bin
YB
Kim
Yong-Hoon
YH
Seo
Woo-Young
WY
Lee
Min-Woo
MW
Lee
Chul Ho
CH
Koo
Seung-Hoi
SH
Choi
Hueng-Sik
HS
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010770:Phosphotransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D001786:Blood Glucose; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; C539967:Nr0b1 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D010770:Phosphotransferases; D005952:Glucose-6-Phosphatase