Liver X receptors interact with corepressors to regulate gene expression
Liver X receptors interact with corepressors to regulate gene expression
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DOI：
10.1210/me.2002-0399
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发表时间：
2003-06-01
影响因子：
--
通讯作者：
Lala, DS
中科院分区：
文献类型：
--
作者：
Hu, X;Li, SZ;Lala, DS
肝X受体（LXR）是核受体超家族的成员，其响应于氧固醇调节基因表达，并通过调节参与胆固醇转运、catalysts和甘油三酯合成的基因在胆固醇稳态中起关键作用。氧固醇和合成激动剂结合LXR并通过募集共激活蛋白来激活转录。在没有配体的情况下，LXR在调节靶基因表达中的作用尚不清楚。在这里，我们表明，LXR相互作用的辅阻遏物，N-CoR（核受体辅阻遏物）和SMRT（沉默介质的维甲酸受体和甲状腺受体），这是释放后结合激动剂。LXR-辅阻遏物相互作用是同种型选择性的，其中LXR α与辅阻遏物具有非常强的相互作用，而LXR β仅显示弱相互作用。LXR还表现出与N-CoR相对于SMRT相互作用的偏好。与其他核受体类似，LXR螺旋3和4区域的突变消除了辅阻遏物的相互作用。使用瞬时转染试验，我们证明，LXR抑制转录，可以通过将N-CoR共转染到细胞中进一步增加。染色质免疫沉淀实验进一步表明，N-CoR被募集到内源性LXR靶基因上，并且添加LXR激动剂从其启动子释放N-CoR。总的来说，这些结果表明，辅阻遏物在调节LXR靶基因表达中起着重要作用。
Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate gene expression in response to oxysterols and play a critical role in cholesterol homeostasis by regulating genes that are involved in cholesterol transport, catabolism, and triglyceride synthesis. Oxysterols and synthetic agonists bind LXRs and activate transcription by recruiting coactivator proteins. The role of LXRs in regulating target gene expression in the absence of ligand is unknown. Here we show that LXRs interact with corepressors, N-CoR ( nuclear receptor corepressor) and SMRT ( silent mediator of retinoic acid receptor and thyroid receptor), which are released upon binding agonists. The LXR-corepressor interaction is isoform selective, wherein LXRalpha has a very strong interaction with corepressors and LXRbeta only shows weak interaction. LXRs also exhibit a preference for interacting with N-CoR vs. SMRT. Similar to other nuclear receptors, mutations in the LXR helix 3 and 4 region abolish corepressor interaction. Using a transient transfection assay, we demonstrate that LXR represses transcription that can be further increased by cotransfecting N-CoR into cells. Chromatin immunoprecipitation experiments further indicated that N-CoR is recruited onto endogenous LXR target genes, and addition of LXR agonists releases N-CoR from their promoters. Collectively, these results suggest that corepressors play an important role in regulating LXR target gene expression.