An extract from date palm fruit (Phoenix dactylifera) acts as a co-agonist ligand for the nuclear receptor FXR and differentially modulates FXR target-gene expression in vitro

PLoS One. 2018 Jan 2;13(1):e0190210. doi: 10.1371/journal.pone.0190210. eCollection 2018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Humans
  • In Vitro Techniques
  • Ligands
  • Phoeniceae / chemistry*
  • Plant Extracts / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / genetics

Substances

  • Ligands
  • Plant Extracts
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor

Grants and funding

Funding was provided by the California Date Commission, Project numbers: 1321-153-07BN and 1321-153-07BB, to Dr. Marie-Louise Ricketts. Christian G. Krueger and Jess D. Reed have ownership interests in Complete Phytochemical Solutions LLC, and in full disclosure, their affiliation with this company is acknowledged in the author affiliation. The funder provided support for research only and did not provide support in the form of salaries, and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “author contributions” section.