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Nedumaran, Balachandar,Hong, Sungpyo,Xie, Yuan-Bin,Kim, Yong-Hoon,Seo, Woo-Young,Lee, Min-Woo,Lee, Chul Ho,Koo, Seung-Hoi,Choi, Hueng-Sik American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.40
<P>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.</P>
Yun-Yong Park,Hueng-Sik Choi,Ju-Seog Lee 한국분자세포생물학회 2010 Molecules and cells Vol.30 No.5
Nuclear receptors (NRs) play pivotal roles in cell growth, proliferation, differentiation and homeostasis. Recent progress demonstrates that NR is tightly linked to human disease such as cancer, diabetes and obesity. Here we explore NR expression profiles in human tissue using systematic approaches. NR gene profiles reveal that individual NR has its own gene expression signature depending on tissue type. Of many organs, NRs expression is enriched in liver. Expression of many NRs was significantly changed in liver cancer. Notably, NR0B2/SHP expression level was significantly decreased in human liver cancer but not in normal liver. In addition, expression of SHP is well associated with good prognosis. SHP gene network analysis based on microarray data in liver cancer shows that SHP regulates cell proliferation and metabolism related gene sets. Our systematic approaches suggest that loss of SHP expression in liver might be key genetic events during hepatocarcinogenesis.
Role of Orphan Nuclear Receptors in The Regulation of Leydig Cell Steroidogenesis
Song, Kwang-Hoon,Choi, Hueng-Sik 이화여자대학교 세포신호전달연구센터 2003 고사리 세포신호전달 심포지움 Vol. No.5
We have recently shown that the orphan nuclear receptor Nur77 plays a key role in regulating the steroidogenesis in testicular Leydig cells. Small heterodimer partner(SHP) is an atypical nuclear receptor that contains a putative ligand-binding domain but lacks a conserved DNA-binding domain and has been proposed to act as a negative regulator of nuclear receptor transactivation. In the present study, we show that SHP interacts directly with Nur77 and represses Nur77-mediated tansactivation. Physical interaction between Nur77 and SHP was confirmed in vitro in a yeast two-hybrid assay and in vivo by co-immunoprecipitation assay indicate that SHP interacts with the DNA-binding domain of Nur77 and represses transcription. Moreover, Northern blot analysis revealed that the expression of Nur77 and CYP17 mRNA was simultaneously increased after puberty during mouse testis development. LH treatment induced immediate-early increase of Nur77 mRNA and delayed-late increase of SHP mRNA. Finally, SHP represses both LH- and Nur77-induced CYP17 promoter activity. Taken together, this study supports a role of Nur77 and SHP interaction in regulation of Leydig cells steroidogenesis