title: DAX1 suppresses FXR transactivity as a novel co-repressor.
abstract: Bile acid receptor FXR (farnesoid X receptor) is a key regulator of hepatic bile acid, glucose and lipid homeostasis through regulation of numerous genes involved in the process of bile acid, triglyceride and glucose metabolism. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains and acts primarily as a co-repressor of many nuclear receptors. Here, we demonstrated that DAX1 is co-localized with FXR in the nucleus and acted as a negative regulator of FXR through a physical interaction with FXR. Our study showed that over-expression of DAX1 down-regulated the expression of FXR target genes, whereas knockdown of DAX1 led to their up-regulation. Furthermore, three LXXLL motifs in the N-terminus of DAX1 were required for the full repression of FXR transactivation. In addition, our study characterized that DAX1 suppresses FXR transactivation via competing with co-activators such as SRC-1 and PGC-1α. In conclusion, DAX1 acts as a co-repressor to negatively modulate FXR transactivity.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Ruya
authors.initials: R
authors.lastname: Liu
authors.forename: Xuelian
authors.initials: X
authors.lastname: Xiong
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000099150:Receptor, Farnesoid X-Activated; C539965:NR0B1 protein, human