Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway
Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway
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DOI：
10.1172/jci73419
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发表时间：
2014-05-01
影响因子：
15.9
通讯作者：
Hollenberg, Anthony N.
中科院分区：
文献类型：
--
作者：
Astapova, Irina;Ramadoss, Preeti;Hollenberg, Anthony N.
转录核心因子是核受体（NR）信号转导机制的重要组成部分，为NR活性的调节提供了额外的机制。在肝脏中缺乏2个NR相互作用结构域（NCoR Delta ID）的突变核辅阻遏物1（NCoR1）的表达导致由甲状腺激素受体（TR）和肝脏X受体（LXR）调节的基因的表达升高，这两者都控制肝脏胆固醇代谢。在这里，我们证明了小鼠肝脏中NCoR Delta ID的表达以LXR α非依赖性方式改善了饮食胆固醇耐受性。NCoR Delta ID相关胆固醇耐受性主要是由于胆盐池的组成和疏水性变化导致肠胆固醇吸收减少。胆盐池的改变是由编码胆汁酸代谢酶CYP27A1和CYP3A11以及小管胆盐泵ABCB 11的基因表达增加介导的。我们已经确定这些基因受甲状腺激素调节，TR β 1被募集到它们的调节区域。总之，这些数据表明，NCoR1和TR之间的相互作用控制参与调节胆固醇代谢和清除的特定途径。
Transcriptional core tors are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoR Delta ID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoR Delta ID in mouse liver improves dietary cholesterol tolerance in an LXR alpha-independent manner. NCoR Delta ID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TR beta 1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance.