Identification of gene-selective modulators of the bile acid receptor FXR
Identification of gene-selective modulators of the bile acid receptor FXR
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DOI：
10.1074/jbc.m209863200
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发表时间：
2003-02-28
影响因子：
4.8
通讯作者：
Forman, BM
中科院分区：
文献类型：
--
作者：
Dussault, I;Beard, R;Forman, BM
BAR是一种核胆汁酸受体（BAR）（FXR）受体，调节胆固醇和胆汁酸稳态相关的基因网络。我们已经确定了两类差异调节BAR活性的合成化合物。第一类以预测的方式激活BAR靶基因，并且比内源性胆汁酸更有效25倍。第二类，以AGN34为代表，在瞬时报告分析中拮抗BAR。令人惊讶的是，该化合物在体内以基因选择性方式起作用：它是CYP7A1的激动剂，IBABP的拮抗剂，并且对SHP是中性的。这些发现表明，可以开发合成BAR调节剂以基因特异性方式调节转录。鉴于BAR调节几种脂质稳态途径的能力，基因选择性BAR调节剂的鉴定对于开发改进的降胆固醇剂具有重要意义。
BAR is a nuclear bile acid receptor (BAR) (FXR) receptor that regulates gene networks involved in cholesterol and bile acid homeostasis. We have identified two classes of synthetic compounds that differentially modulate BAR activity. The first class activates BAR target genes in the predicted fashion and is 25-fold more potent than endogenous bile acids. The second class, represented by AGN34, antagonizes BAR in transient reporter assays. Surprisingly, this compound acts in a gene-selective manner in vivo: it is an agonist on CYP7A1, an antagonist on IBABP, and is neutral on SHP. These findings indicate that synthetic BAR modulators can be developed to regulate transcription in a gene-specific fashion. Given the ability of BAR to regulate several lipid homeostatic pathways, the identification of gene-selective BAR modulators have important implications for the development of improved cholesterol lowering agents.