作为 TGR5 受体激动剂的海洋胆汁天然产物,Journal of Natural Products

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作为 TGR5 受体激动剂的海洋胆汁天然产物
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-04-27 , DOI: 10.1021/acs.jnatprod.0c01327
Christopher Halkias ₁ , William G Darby ₁ , Bryce N Feltis ₁ , Peter McIntyre _{1,

2} , Theodore A Macrides ₁ , Paul F A Wright ₁

Affiliation

G 蛋白偶联胆汁酸受体“武田 G 蛋白受体 5”（TGR5）的激动作用有助于减轻由于动脉粥样硬化进展引起的胆固醇积累。虽然哺乳动物胆汁化合物可以激活TGR5，但它们通常是弱激动剂，需要鉴定更有效的化合物。在本研究中，两种海洋胆汁化合物（5β-莨菪醇及其硫酸盐）与哺乳动物胆汁化合物脱氧胆酸 (DCA) 和熊去氧胆酸 (UDCA) 进行了比较。TGR5 激动的模型。将转染过表达 TGR5 (HEK293-TGR5) 并与亚细胞毒性浓度的测试化合物一起孵育的人胚胎肾 293 细胞 (HEK293) 的反应曲线与未转染的 HEK293 对照细胞进行比较，使用特定的钙结合荧光团 Fura-2AM 来测量细胞内钙[Ca ²⁺ ]_我释放。Scymnol 和 scymnol 硫酸盐仅导致TGR5 细胞内[Ca ²⁺ ] _i的持续增加，这被 G _αq蛋白的特异性抑制剂(UBO-QIC)消除。[Ca ²⁺ ] _i持续增加在 DCA 暴露的两种细胞类型中都观察到；这不受 UBO-QIC 的影响，表明不涉及 TGR5 激活。暴露于 UDCA 并没有改变 [Ca ²⁺ ] _i，表明缺乏 TGR5 生物活性。这些发现表明，scymnol 和 scymnol 硫酸盐都是 TGR5 受体的新型激动剂，显示出治疗动脉粥样硬化的潜力。

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Marine Bile Natural Products as Agonists of the TGR5 Receptor

Agonism of the G protein-coupled bile acid receptor “Takeda G-protein receptor 5” (TGR5) aids in attenuating cholesterol accumulation due to atherosclerotic progression. Although mammalian bile compounds can activate TGR5, they are generally weak agonists, and more effective compounds need to be identified. In this study, two marine bile compounds (5β-scymnol and its sulfate) were compared with mammalian bile compounds deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) using an in vitro model of TGR5 agonism. The response profiles of human embryonic kidney 293 cells (HEK293) transfected to overexpress TGR5 (HEK293-TGR5) and incubated with subcytotoxic concentrations of test compounds were compared to nontransfected HEK293 control cells using the specific calcium-binding fluorophore Fura-2AM to measure intracellular calcium [Ca²⁺]_i release. Scymnol and scymnol sulfate caused a sustained increase in [Ca²⁺]_i within TGR5 cells only, which was abolished by a specific inhibitor for G_αq protein (UBO-QIC). Sustained increases in [Ca²⁺]_i were seen in both cell types with DCA exposure; this was unaffected by UBO-QIC, indicating that TGR5 activation was not involved. Exposure to UDCA did not alter [Ca²⁺]_i, suggesting a lack of TGR5 bioactivity. These findings demonstrated that both scymnol and scymnol sulfate are novel agonists of TGR5 receptors, showing therapeutic potential for treating atherosclerosis.

更新日期：2021-05-28

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