Orphan Nuclear Receptor DAX-1 Acts as a Novel Corepressor of Liver X Receptor α and Inhibits Hepatic Lipogenesis

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical regionon 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 4 alpha 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 (LXR alpha). Physical interaction between DAX-1 and LXR alpha was confirmed Immunofluorescent staining in mouse liver shows that LXR alpha 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 LXR alpha. Competition analyses demonstrate that DAX1 competes with the coactivator SRC-1 for repressing LXR alpha transactivity. Chromatin immunoprecipitation assay showed that endogenous DAX-1 recruitment on the SREBP-1c gene promoter was decreased in the presence of LXR alpha agonist. Overexpression of DAX-1 inhibits T7-induced LXR alpha target gene expression, whereas knockdown of endogenous DAX-1 significantly increases T7-induced LXR alpha target gene expression in HepG2 cells. Finally, overexpression of DAX-1 in mouse liver decreases T7-induced LXR alpha target gene expression, liver triglyceride level, and lipid accumulation. Overall, this study suggests that DAX-1, a novel corepressor of LXR alpha, functions as a negative regulator of lipogenic enzyme gene expression in liver.