DAX1 suppresses FXR transactivity as a novel co-repressor
DAX1 suppresses FXR transactivity as a novel co-repressor
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DAX1 作为新型共阻遏物抑制 FXR 反式活性
DOI：
10.1016/j.bbrc.2011.08.020
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发表时间：
2011-09-09
影响因子：
3.1
通讯作者：
Li, Xiaoying
中科院分区：
文献类型：
--
作者：
Li, Jin;Lu, Yan;Li, Xiaoying
胆汁酸受体FXR（farnesoid X receptor）是通过调节胆汁酸、甘油三酯和葡萄糖代谢过程中涉及的众多基因来调节肝脏胆汁酸、葡萄糖和脂质稳态的关键调节因子。DAX 1（dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome，gene 1）是核受体家族的一个非典型成员，由于缺乏经典的DNA结合结构域，主要作为许多核受体的共阻遏物。在这里，我们证明了DAX 1与FXR在细胞核中共定位，并通过与FXR的物理相互作用作为FXR的负调节因子。我们的研究表明，DAX 1的过表达下调FXR靶基因的表达，而DAX 1的敲低导致其上调。此外，在DAX 1的N-末端的三个LXXLL基序需要FXR反式激活的完全抑制。此外，我们的研究特征在于DAX 1通过与辅激活剂如SRC-1和PGC-1 α竞争来抑制FXR反式激活。总之，DAM作为一个辅助阻遏物负调节FXR的反式活性。(C)2011 Elsevier Inc. All rights reserved.
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-1 alpha. In conclusion, DAM acts as a co-repressor to negatively modulate FXR transactivity. (C) 2011 Elsevier Inc. All rights reserved.