Department of Food Science, New Jersey Institute for Food, Nutrition, and Health (Rutgers Center for Lipid Research and Center for Nutrition, Microbiome, and Health), Rutgers University, New Brunswick, New Jersey, USA.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey, USA.
J Biomol Struct Dyn. 2024 May;42(8):4249-4262. doi: 10.1080/07391102.2023.2224886. Epub 2023 Jun 20.
Bile acids (BAs) act as signaling molecules 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 changes to gut bacteria, or alteration of ligand-availability BA sequestration. Herein, we used an 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）作为信号分子，与各种核（FXR、VDR、PXR 和 CAR）和 G 蛋白偶联（TGR5、M3R、S1PR2）BA 受体相互作用。这些 BA 受体的刺激会影响多种过程，包括炎症反应和葡萄糖及外源性物质代谢。在心脏代谢疾病中，胆汁酸谱和 BA 受体活性失调；然而，饮食中的多酚已被证明可以改变胆汁酸谱和信号，从而改善代谢表型。我们之前曾报道，用富含原花青素（PAC）的葡萄多酚（GP）提取物补充小鼠可减轻葡萄糖不耐受的症状，同时改变胆汁酸谱、BA 受体基因表达和/或 BA 受体活性的下游标志物。多酚调节 BA 信号的确切机制尚不清楚，但一些假设包括调节胆汁酸谱、肠道细菌的变化，或改变配体可用性、BA 结合。在此，我们采用计算方法研究原花青素 B2（PACB2）及其代谢物与核和 G 蛋白偶联 BA 受体的潜在结合亲和力。分子对接和动力学模拟表明，某些 PACB2 代谢物与 S1PR2、PXR 和 CAR 具有稳定的结合亲和力，与已知的天然和合成 BA 配体相当。这些发现表明，PACB2 代谢物可能是 S1PR2、CAR 和 PXR 受体的新型配体。由 Ramaswamy H. Sarma 交流。
