FLG249 Exhibits FXR Antagonist Activity by Inducing Dissociation of Both Corepressors and Coactivators from FXR.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Yusuke Iguchi, Yukiko Yamashita, Keigo Gohda, Ko Fujimori, Yukihiro Sera, Tsuneo Imanaka, Masafumi Yamaguchi, Mizuho Une, Naoki Teno
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Abstract

The farnesoid X receptor (FXR), a nuclear receptor activated by endogenous bile acids, regulates not only bile acid synthesis but also lipid and carbohydrate metabolism. Therefore, FXR ligands, including FXR antagonists, show potential as therapeutic agents for various metabolic diseases. However, the mechanism by which FXR antagonists influence FXR activity is unclear. We previously synthesized an FXR antagonist, FLG249, which reduced the expression of several FXR target genes in the mouse ileum when orally administered and improved lipid metabolism in the liver and ileum of high-fat diet-induced obese mice. In the present study, we aimed to characterize the mechanism by which FLG249 inhibits the interaction of FXR with its coactivators and corepressors. The LanthaScreenTM time-resolved fluorescence energy transfer assay and two-hybrid assay were used to evaluate the effect of FLG249 on FXR. We found that, upon binding, FLG249 reduced the interaction of FXR with both coactivators and corepressors. This result suggests that the mechanism of FLG249 as a nuclear receptor modulator is distinct from that of previously reported neutral antagonists and inverse agonists of nuclear receptors.

FLG249通过诱导辅抑制因子和辅激活因子从FXR中解离而表现出FXR拮抗剂活性。
farnesoid X受体(FXR)是一种由内源性胆汁酸激活的核受体,不仅调节胆汁酸的合成,还调节脂质和碳水化合物的代谢。因此,FXR配体,包括FXR拮抗剂,显示出作为各种代谢性疾病治疗剂的潜力。然而,FXR拮抗剂影响FXR活性的机制尚不清楚。我们之前合成了一种FXR拮抗剂FLG249,当口服给药时,它降低了小鼠回肠中几个FXR靶基因的表达,并改善了高脂肪饮食诱导的肥胖小鼠肝脏和回肠的脂质代谢。在本研究中,我们旨在描述FLG249抑制FXR与其共激活因子和共抑制因子相互作用的机制。采用LanthaScreenTM时间分辨荧光能量转移法和双杂交法评价FLG249对FXR的影响。我们发现,结合后,FLG249减少了FXR与共激活子和共抑制子的相互作用。这一结果表明,FLG249作为核受体调节剂的机制不同于先前报道的核受体中性拮抗剂和逆激动剂。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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