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,Yong-Hoon Kim,Young Chul Lee,Chul-Ho Lee,Seung-Hoi Koo,Young-Sil Yoon,Hueng-Sik Choi

doi:10.1074/jbc.m109.073650

Abstract

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) 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 4alpha 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 alpha (LXRalpha). Physical interaction between DAX-1 and LXRalpha was confirmed Immunofluorescent staining in mouse liver shows that LXRalpha 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 LXRalpha. Competition analyses demonstrate that DAX-1 competes with the coactivator SRC-1 for repressing LXRalpha transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXRalpha agonist. Overexpression of DAX-1 inhibits T7-induced LXRalpha target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXRalpha target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXRalpha target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXRalpha, functions as a negative regulator of lipogenic enzyme gene expression in liver.

Highlights

Nuclear receptors are a class of DNA binding transcription factors that regulate gene expression and play important roles in a variety of biological and pathological processes [2]
LXR is known to induce the expression of SREBP-1c, a transcription factor that regulates the expression of various lipogenic genes, including those encoding acetyl-coenzyme A carboxylase and fatty-acid synthase (FAS) [22]
These results indicate that DAX-1 is expressed in liver, and it inhibits the transcriptional activity of LXR␣

Summary

Introduction

Nuclear receptors are a class of DNA binding transcription factors that regulate gene expression and play important roles in a variety of biological and pathological processes [2]. We have previously reported that DAX-1 can negatively regulate the expression of gluconeogenic genes by inhibiting the transcriptional activity of hepatocyte nuclear factor 4 ␣ (HNF4␣) [1]. We found that DAX-1 dose-dependently decreased the reporter activity containing the LXR-binding site (LXRE-Luc) induced by LXR␣ in the presence of its synthetic agonist T0901317 (Fig. 1B).

Results

Conclusion