Introduction

The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases.

Objectives

The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells.

Methods

OCA was conjugated to an iridium(III) complex to generate the novel complex 1. The effect of complex 1 on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex 1 were assessed for FXR imaging.

Results

Complex 1 retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA’s activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells.

Conclusion

The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex 1 retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA’s activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.

中文翻译：

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通过铱 （III） 复合物偶联来定制奥贝胆酸活性以开发法尼醇 X 受体探针

 介绍

法尼醇 X 受体 （FXR） 是肠道中的重要调节因子，可维持胆汁酸稳态。抑制肠道 FXR 通过减少胆汁酸积累，有望控制炎症性肠病和肝病。此外，FXR 表达的变化可以作为肠道疾病的潜在生物标志物。因此，开发 FXR 成像探针对 FXR 相关疾病的早期检测、同步治疗和监测具有重要潜力。

 目标

该研究旨在通过将 FXR 激动剂奥贝胆酸 （OCA） 与铱 （III） 复合物偶联来开发一种用于 FXR 的生物成像探针，并研究其在肠道细胞中靶向 FXR 的应用。

 方法

OCA 与铱 （III） 配合物偶联以生成新型配合物 1。使用各种生化和细胞测定在肠上皮细胞中研究复合物 1 对 FXR 活性、核转位和下游靶标的影响。此外，还评估了复合物 1 的光物理特性以进行 FXR 成像。

 结果

复合物 1 保留了监测肠道细胞中 FXR 的理想光物理特性，同时将 OCA 的活性从激动性逆转为拮抗性。它破坏了 FXR-RXR 异二聚化，抑制了 FXR 核转位，并下调了负责肠上皮细胞中胆汁酸吸收、运输和代谢的下游靶标。

 结论

该研究通过将 OCA 与铱 （III） 复合物偶联，成功开发了 FXR 的成像探针和调节剂。复合物 1 保留了铱 （III） 复合物的良好光物理特性，同时将 OCA 的活性从激动性逆转为拮抗性。这些发现强调了使用金属来定制生命系统中核受体调节剂活性的令人兴奋的应用。