Proanthocyanidin B2 derived metabolites may be ligands for bile acid receptors S1PR2, PXR and CAR: an in silico approach

Bile acids (BAs) act as signaling molecules via their interactions with various nuclear (FXR, VDR, PXR and CAR) and G-protein coupled (TGR5, M3R, S1PR2) BA receptors. Stimulation of these BA receptors influences several processes, including inflammatory responses and glucose and xenobiotic metabolism. BA profiles and BA receptor activity are deregulated in cardiometabolic diseases; however, dietary polyphenols were shown to alter BA profile and signaling in association with improved metabolic phenotypes. We previously reported that supplementing mice with a proanthocyanidin (PAC)-rich grape polyphenol (GP) extract attenuated symptoms of glucose intolerance in association with changes to BA profiles, BA receptor gene expression, and/or downstream markers of BA receptor activity. Exact mechanisms by which polyphenols modulate BA signaling are not known, but some hypotheses include modulation of the BA profile via changes to gut bacteria, or alteration of ligand-availability via BA sequestration. Herein, we used an in silico approach to investigate putative binding affinities of proanthocyanidin B2 (PACB2) and PACB2 metabolites to nuclear and G-protein coupled BA receptors. Molecular docking and dynamics simulations revealed that certain PACB2 metabolites had stable binding affinities to S1PR2, PXR and CAR, comparable to that of known natural and synthetic BA ligands. These findings suggest PACB2 metabolites may be novel ligands of S1PR2, CAR, and PXR receptors. Communicated by Ramaswamy H. Sarma

胆汁酸（BAs）可通过与多种核受体（FXR、VDR、PXR及CAR）以及G蛋白偶联型BA受体（TGR5、M3R、S1PR2）结合，发挥信号分子功能。此类BA受体的激活可调控诸多生理过程，涵盖炎症反应、葡萄糖代谢与异生物质代谢。心血管代谢疾病患者的BA谱及BA受体活性常出现失调；不过已有研究证实，膳食多酚可通过重塑BA谱与BA信号通路，改善机体代谢表型。本团队此前的研究显示，给小鼠饲喂富含原花青素（PAC）的葡萄多酚（GP）提取物，可通过改变BA谱、BA受体基因表达及/或BA受体活性的下游标志物，缓解小鼠的糖耐量异常症状。目前学界尚未明确多酚调控BA信号通路的确切机制，现有假说包括通过改变肠道菌群调节BA谱，或通过BA螯合作用改变配体可及性。本研究采用计算机模拟（in silico）方法，探究了原花青素B2（PACB2）及其代谢产物与核受体及G蛋白偶联型BA受体的潜在结合亲和力。分子对接与分子动力学模拟结果显示，部分PACB2代谢产物与S1PR2、PXR及CAR具有稳定的结合亲和力，其强度可与已知天然及合成BA配体相媲美。上述结果表明，PACB2代谢产物可能是S1PR2、CAR及PXR受体的新型配体。本文由Ramaswamy H. Sarma转交刊发。