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Rev-erb regulation of cholesterologenesis

机译：Rev-ERB对胆固醇的调节

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REV-ERBc and REV-ERB beta 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-methylglutaryl-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 C57B1/6 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 these data, we observed increased expression of these genes in mice deficient in expression of Rev-erb alpha. 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. (C) 2017 Elsevier Inc. All rights reserved.
机译：Rev-ERBC和Rev-ERBβ是血红素调节的核受体，已知调节代谢途径。我们以前证明，用合成Rev-ERB激动剂的小鼠治疗抑制血浆胆固醇水平和胆固醇生物合成中的速率限制酶的肝水平（3-羟基-3-甲基戊齐辅酶还原酶）。在这里，我们更详细地表征Rev-ERB对胆固醇生物合成途径的作用。 Rev-ERB激动剂SR9009在野生型C57B1 / 6和低密度脂蛋白受体（LDLR）含氟小鼠中减少血浆胆固醇水平，以及降低胆固醇生物合成途径内的基因阵列的表达。与这些数据一致，我们观察到缺乏缺乏Rev-ERBα的小鼠中这些基因的增加。全局续集和深度测序（GRO-SEQ）和染色质免疫沉淀的深度测序（CHIP-SEQ）数据的分析显示，REV-ERB直接与胆固醇生物合成中涉及的大多数基因结合，并直接抑制其表达。本研究揭示了对复杂机制的洞察力，通过该机制直接和间接地（通过抑制SrebF2表达）调节胆固醇生物合成，并提供胆固醇水平如何以昼夜方式调节胆固醇水平的信息。另外，这些研究表明，靶向Rev-ERB可能是抑制临床中LDL胆固醇水平的有效方法。 （c）2017年Elsevier Inc.保留所有权利。

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