NNF Center for Basic Metabolic Research, Nutrient and Metabolite Sensing Program, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Molecules. 2020 May 20;25(10):2371. doi: 10.3390/molecules25102371.
Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are the two known bile acid (BA) sensitive receptors and are expressed in the intestine and liver as well as in extra-enterohepatic tissues. The physiological effects of extra-enterohepatic FXR/TRG5 remain unclear. Further, the extent BAs escape liver reabsorption and how they interact with extra-enterohepatic FXR/TGR5 is understudied. We investigated if hepatic BA reuptake differed between BAs agonistic for FXR and TGR5 compared to non-agonists in the rat. Blood was collected from the portal vein and inferior caval vein from anesthetized rats before and 5, 20, 30, and 40 min post stimulation with sulfated cholecystokinin-8. Plasma concentrations of 20 different BAs were assessed by liquid chromatography coupled to mass spectrometry. Total portal vein BA AUC was 3-4 times greater than in the vena cava inferior (2.7 ± 0.6 vs. 0.7 ± 0.2 mM x min, < 0.01, n = 8) with total unconjugated BAs being 2-3-fold higher than total conjugated BAs (AUC 8-10 higher < 0.05 for both). However, in both cases, absolute ratios varied greatly among different BAs. The average hepatic reuptake of BAs agonistic for FXR/TGR5 was similar to non-agonists. However, as the sum of non-agonist BAs in vena portae was 2-3-fold higher than the sum agonist ( < 0.05), the peripheral BA pool was composed mostly of non-agonist BAs. We conclude that hepatic BA reuptake varies substantially by type and does not favor FXR/TGR5 BAs agonists.
法尼醇 X 受体 (FXR) 和 Takeda G 蛋白偶联受体 5 (TGR5) 是两种已知的胆汁酸 (BA) 敏感受体，在肠道和肝脏以及肠外组织中表达。肠外 FXR/TRG5 的生理作用尚不清楚。此外，BA 逃避肝脏重吸收的程度以及它们与肠外 FXR/TGR5 的相互作用尚未得到充分研究。我们研究了在大鼠中，与非激动剂相比，FXR 和 TGR5 的激动剂 BA 是否会导致肝摄取 BA 不同。在麻醉大鼠中，用硫酸胆囊收缩素-8 刺激前和刺激后 5、20、30 和 40 分钟，从门静脉和下腔静脉采集血液。通过液相色谱-质谱联用评估 20 种不同 BA 的血浆浓度。门静脉总 BA AUC 是下腔静脉总 BA AUC 的 3-4 倍（2.7 ± 0.6 对 0.7 ± 0.2 mM x min， < 0.01，n = 8），总非结合 BA 比总结合 BA 高 2-3 倍（AUC 分别高 8-10 倍，均 < 0.05）。然而，在这两种情况下，不同 BA 之间的绝对比值差异很大。FXR/TGR5 激动剂 BA 的平均肝摄取与非激动剂相似。然而，由于门静脉中非激动剂 BA 的总和是激动剂的 2-3 倍（ < 0.05），外周 BA 池主要由非激动剂 BA 组成。我们得出结论，肝 BA 摄取的类型差异很大，并不有利于 FXR/TGR5 BA 激动剂。
