Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor α and inhibits hepatic lipogenesis

Balachandar Nedumaran, Gwang Sik Kim, Sungpyo Hong, Young Sil Yoon, Yong Hoon Kim, Chul Ho Lee, Young Chul Lee, Seung-Hoi Koo, Hueng Sik Choi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene1) is a member of the nuclear receptor superfamily that can repress diverse nuclear receptors and has a key role in adreno-gonadal development. Our previous report has demonstrated that DAX-1 can inhibit hepatocyte nuclear factor 4α transactivity and negatively regulate gluconeogenic gene expression (Nedumaran, B., Hong, S., Xie, Y. B., Kim, Y. H., Seo, W. Y., Lee, M. W., Lee, C. H., Koo, S. H., and Choi, H. S. (2009) J. Biol. Chem. 284, 27511-27523). Here, we further expand the role of DAX-1 in hepatic energy metabolism. Transfection assays have demonstrated that DAX-1 can inhibit the transcriptional activity of nuclear receptor liver X receptor α (LXRα). Physical interaction between DAX-1 and LXRα was confirmed Immunofluorescent staining in mouse liver shows that LXRα and DAX-1 are colocalized in the nucleus. Domain mapping analysis shows that the entire region of DAX-1 is involved in the interaction with the ligand binding domain region of LXRα. Competition analyses demonstrate that DAX-1 competes with the coactivator SRC-1 for repressing LXRα transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXRα agonist. Overexpression of DAX-1 inhibits T7-induced LXRα target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXRα target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXRα target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXRα, functions as a negative regulator of lipogenic enzyme gene expression in liver.

Original languageEnglish
Pages (from-to)9221-9232
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
Publication statusPublished - 2010 Mar 19
Externally publishedYes

Fingerprint

DAX-1 Orphan Nuclear Receptor
Co-Repressor Proteins
Lipogenesis
Liver
Gene expression
Gene Expression
Cytoplasmic and Nuclear Receptors
Hepatocyte Nuclear Factor 4
Liver X Receptors
Sterol Regulatory Element Binding Protein 1
Assays
Chromatin Immunoprecipitation
Hep G2 Cells
X Chromosome

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Nedumaran, B., Kim, G. S., Hong, S., Yoon, Y. S., Kim, Y. H., Lee, C. H., ... Choi, H. S. (2010). Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor α and inhibits hepatic lipogenesis. Journal of Biological Chemistry, 285(12), 9221-9232. https://doi.org/10.1074/jbc.M109.073650

Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor α and inhibits hepatic lipogenesis. / Nedumaran, Balachandar; Kim, Gwang Sik; Hong, Sungpyo; Yoon, Young Sil; Kim, Yong Hoon; Lee, Chul Ho; Lee, Young Chul; Koo, Seung-Hoi; Choi, Hueng Sik.

In: Journal of Biological Chemistry, Vol. 285, No. 12, 19.03.2010, p. 9221-9232.

Research output: Contribution to journalArticle

Nedumaran, Balachandar ; Kim, Gwang Sik ; Hong, Sungpyo ; Yoon, Young Sil ; Kim, Yong Hoon ; Lee, Chul Ho ; Lee, Young Chul ; Koo, Seung-Hoi ; Choi, Hueng Sik. / Orphan nuclear receptor DAX-1 acts as a novel corepressor of liver X receptor α and inhibits hepatic lipogenesis. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 12. pp. 9221-9232.
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abstract = "DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene1) is a member of the nuclear receptor superfamily that can repress diverse nuclear receptors and has a key role in adreno-gonadal development. Our previous report has demonstrated that DAX-1 can inhibit hepatocyte nuclear factor 4α transactivity and negatively regulate gluconeogenic gene expression (Nedumaran, B., Hong, S., Xie, Y. B., Kim, Y. H., Seo, W. Y., Lee, M. W., Lee, C. H., Koo, S. H., and Choi, H. S. (2009) J. Biol. Chem. 284, 27511-27523). Here, we further expand the role of DAX-1 in hepatic energy metabolism. Transfection assays have demonstrated that DAX-1 can inhibit the transcriptional activity of nuclear receptor liver X receptor α (LXRα). Physical interaction between DAX-1 and LXRα was confirmed Immunofluorescent staining in mouse liver shows that LXRα and DAX-1 are colocalized in the nucleus. Domain mapping analysis shows that the entire region of DAX-1 is involved in the interaction with the ligand binding domain region of LXRα. Competition analyses demonstrate that DAX-1 competes with the coactivator SRC-1 for repressing LXRα transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXRα agonist. Overexpression of DAX-1 inhibits T7-induced LXRα target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXRα target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXRα target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXRα, functions as a negative regulator of lipogenic enzyme gene expression in liver.",
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