Insights in the regulation of cholesterol 7αHydroxylase gene reveal a target for modulating bile acid synthesis
Insights in the regulation of cholesterol 7αHydroxylase gene reveal a target for modulating bile acid synthesis
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DOI：
10.1002/hep.21819
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发表时间：
2007-09-01
期刊：
影响因子：
13.5
通讯作者：
Crestani, Maurizio
中科院分区：
文献类型：
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作者：
Mitro, Nico;Godio, Cristina;Crestani, Maurizio
编码胆固醇 7 α-羟化酶（胆固醇稳态中的关键酶）的基因 (CYP7A1) 的转录受到胆汁酸通过涉及核受体超家族成员的多种机制的抑制。在这里，我们描述了一种可用于调节胆汁酸合成的调节机制。通过剖析 CYP7A1 转录机制，我们发现胆汁酸刺激组蛋白脱乙酰酶 (HDAC) 7、3 和 1、辅阻遏物 SMRT α（类视黄醇和甲状腺受体-α 的沉默介质）和核辅阻遏物的顺序募集。胆汁酸（而不是法尼醇 X 受体选择性激动剂 GW4064）会增加 HDAC7 的核浓度，从而促进抑制复合物的组装，最终抑制 CYP7A1 转录。有趣的是，尽管其基础表达水平很高，但小异二聚体伴侣 (SHP) 仅在胆汁酸抑制的后期才与 CYP7A1 启动子相关。小干扰RNA的基因沉默证实HDAC7是抑制CYP7A1转录所需的关键因素，而SHP的敲低并不能阻止CYP7A1的下调。对遗传性高胆固醇血症小鼠施用HDAC抑制剂丙戊酸或曲古抑菌素A会增加Cyp7al信使RNA和胆汁酸的合成，从而显着降低血浆总胆固醇和低密度脂蛋白胆固醇。结论：通过结合分子、细胞和动物模型，我们的研究强调了 HDAC 在 CYP7A1 转录反馈调节中的重要性，并将这些酶确定为调节胆汁酸合成和治疗高胆固醇血症的潜在靶标。
The transcription of the gene (CYP7A1) encoding cholesterol 7 alpha-hydroxylase, a key enzyme in cholesterol homeostasis, is repressed by bile acids via multiple mechanisms involving members of the nuclear receptor superfamily. Here, we describe a regulatory mechanism that can be exploited for modulating bile acid synthesis. By dissecting the mechanisms of CYP7A1 transcription, we found that bile acids stimulate the sequential recruitment of the histone deacetylases (HDACs) 7, 3, and 1, and of the corepressor SMRT alpha (silencing mediator of retinoid and thyroid reccptors-alpha) and the nuclear corepressor. Bile acids, but not the farnesoid X receptor-selective agonist GW4064, increase the nuclear concentration of HDAC7, which promotes the assembly of a repressive complex that ultimately represses CYP7A1 transcription. Interestingly, despite its high basal expression level, small heterodimer partner (SHP) is associated with the CYP7A1 promoter only at a later stage of bile acid repression. Gene silencing with small interfering RNA confirms that HDAC7 is the key factor required for the repression of CYP7A1 transcription, whereas knockdown of SHP does not prevent the down-regulation of CYP7A1 Administration of the HDAC inhibitors valproic acid or trichostatin A to genetically hypercholesterolemic mice increases Cyp7al messenger RNA and bile acid synthesis and consequently markedly reduces total plasma and low-density lipoprotein cholesterol. Conclusion: By using a combination of molecular, cellular, and animal models, our study highlights the importance of HDACs in the feedback regulation of CYP7A1 transcription and identifies these enzymes as potential targets to modulate bile acid synthesis and for the treatment of hypercholesterolemia.