Alfaro-Viquez Emilia, Roling Brent F, Krueger Christian G, Rainey Charlene J, Reed Jess D, Ricketts Marie-Louise
Reed Research Group, Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI, United States of America.
Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, Reno, NV, United States of America.
PLoS One. 2018 Jan 2;13(1):e0190210. doi: 10.1371/journal.pone.0190210. eCollection 2018.
Date palm fruit (Phoenix dactylifera) consumption reduces serum triglyceride levels in human subjects. The objective of this study was to prepare an extract from dates and determine whether it acts as a ligand for the farnesoid x receptor (FXR), a nuclear receptor important for maintaining triglyceride and cholesterol homeostasis. Freeze-dried extracts were isolated from California-grown dates (Deglet Noor and Medjool) from the 2014 and 2015 harvests, by means of liquid extraction and solid phase separation. Each date palm extract (DPE) was characterized via HPLC and MALDI-TOF mass spectrometry, and the procyanidin content was qualitatively determined. Extracts were tested to determine their ability to modulate nuclear receptor-mediated transactivation using transient transfection. The effect of DPE on FXR-target genes regulating bile acid absorption and transport was then assessed in vitro, in Caco-2 cells. Characterization reveals that DPE is a rich source of polyphenols including hydroxycinnamic acids, proanthocyanidins, and lipohilic polyphenols, and comprises 13% proanthocyanidins. Transactivation results show that DPE acts as a co-agonist ligand for both mouse and human FXR, wherein it activates bile acid-bound FXR greater than that seen with bile acid alone. Additionally, DPE alone activated a peroxisome proliferator activated receptor alpha (PPARα) chimera in a dose-dependent manner. Consistent with DPE as a co-agonist ligand for FXR, studies in Caco-2 cells reveal that co-incubation with bile acid, dose-dependently enhances the expression of fibroblast growth factor 19 (FGF19), compared to treatment with bile acid alone. In contrast, DPE inhibited bile acid-induced expression of ileal bile acid binding protein (IBABP). Our results demonstrate that DPE acts as a potent co-agonist ligand for FXR, and that it differentially regulates FXR-target gene expression in vitro in human intestinal cells. This study provides novel insight into a potential mechanism by which dates may exert a hypotriglyceridemic effect via FXR and modulation of bile acid homeostasis.
食用椰枣（Phoenix dactylifera）可降低人体受试者的血清甘油三酯水平。本研究的目的是制备枣提取物，并确定其是否作为法尼酯X受体（FXR）的配体，FXR是一种对维持甘油三酯和胆固醇稳态很重要的核受体。通过液体萃取和固相分离，从2014年和2015年收获的加利福尼亚种植的枣（Deglet Noor和Medjool）中分离出冻干提取物。通过高效液相色谱法（HPLC）和基质辅助激光解吸电离飞行时间质谱法（MALDI-TOF）对每种枣提取物（DPE）进行表征，并定性测定原花青素含量。使用瞬时转染测试提取物调节核受体介导的反式激活的能力。然后在体外Caco-2细胞中评估DPE对调节胆汁酸吸收和转运的FXR靶基因的影响。表征显示DPE是包括羟基肉桂酸、原花青素和亲脂性多酚在内的多酚的丰富来源，并且含有13%的原花青素。反式激活结果表明DPE作为小鼠和人FXR的共激动剂配体，其中它比单独的胆汁酸更能激活与胆汁酸结合的FXR。此外，单独的DPE以剂量依赖性方式激活过氧化物酶体增殖物激活受体α（PPARα）嵌合体。与DPE作为FXR的共激动剂配体一致，在Caco-2细胞中的研究表明，与单独用胆汁酸处理相比，与胆汁酸共同孵育剂量依赖性地增强成纤维细胞生长因子19（FGF19）的表达。相反，DPE抑制胆汁酸诱导的回肠胆汁酸结合蛋白（IBABP）的表达。我们的结果表明DPE作为FXR的有效共激动剂配体，并且它在体外人肠道细胞中差异调节FXR靶基因表达。本研究为枣可能通过FXR和调节胆汁酸稳态发挥降甘油三酯作用的潜在机制提供了新的见解。
