Rev-erb regulation of cholesterologenesis.
Rev-erb regulation of cholesterologenesis.
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DOI：
10.1016/j.bcp.2017.02.006
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发表时间：
2017-05-01
影响因子：
5.8
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Sitaula, Sadichha;Zhang, Jinsong;Ruiz, Fernanda;Burris, Thomas P.
rev - erbb α和rev - erbb β是血红素调节的核受体，已知可调节代谢途径。我们之前证明，用合成REV-ERB激动剂治疗小鼠可抑制血浆胆固醇水平和胆固醇生物合成限速酶（3-羟基-3-甲基戊二酰辅酶a还原酶）的肝脏水平。在这里，我们更详细地描述了REV-ERB在胆固醇生物合成途径中的作用。REV-ERB激动剂SR9009降低了野生型C57Bl/6和低密度脂蛋白受体（LDLR）缺失小鼠的血浆胆固醇水平，并降低了胆固醇生物合成途径中一系列基因的表达。与此数据一致，我们观察到在缺乏rev - erba表达的小鼠中这些基因的表达增加。对全球运行和深度测序（GRO-Seq）和染色质免疫沉淀深度测序（ChIP-Seq）数据的分析显示，Rev-erb直接结合大多数参与胆固醇生物合成的基因并直接抑制其表达。这项研究揭示了Rev-erb直接或间接（通过抑制Srebf2表达）调节胆固醇生物合成的复杂机制，并提供了胆固醇水平如何以昼夜节律方式调节的信息。此外，这些研究表明，靶向Rev-erb可能是临床上抑制LDL胆固醇水平的有效方法。
REV-ERBα and REV-ERBβ are heme regulated nuclear receptors that are known to regulate metabolic pathways. We previously demonstrated that treatment of mice with synthetic REV-ERB agonists suppressed plasma cholesterol levels and the hepatic levels of the rate limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-Mmethylglutaryl-CoA reductase). Here, we characterize the role of REV-ERB on the cholesterol biosynthetic pathway in greater detail. The REV-ERB agonist SR9009 reduced plasma cholesterol levels in both wild type C57Bl/6 and low density lipoprotein receptor (LDLR) null mice as well as reducing the expression of an array of genes within the cholesterol biosynthetic pathway. Consistent with this data, we observed increased expression of these genes in mice deficient in expression of Rev-erbα. Analysis of global run-on and deep sequencing (GRO-Seq) and chromatin immunoprecipitation deep sequencing (ChIP-Seq) data revealed that Rev-erb directly binds to the majority of genes involved in cholesterol biosynthesis and directly suppresses their expression. This study reveals insight into the complex mechanism by which Rev-erb directly and indirectly (via inhibition of Srebf2 expression) regulates cholesterol biosynthesis and provides information of how cholesterol levels are regulated in a circadian fashion. Additionally, these studies suggest that targeting Rev-erb may be an effective method for suppressing LDL cholesterol levels in the clinic.
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影响因子：
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