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

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.

[1]  B. Ferguson,et al.  A grape seed procyanidin extract inhibits HDAC activity leading to increased Ppar&agr; phosphorylation and target‐gene expression , 2017, Molecular nutrition & food research.

[2]  M. Ricketts,et al.  Mechanistic insight into nuclear receptor‐mediated regulation of bile acid metabolism and lipid homeostasis by grape seed procyanidin extract (GSPE) , 2017, Cell biochemistry and function.

[3]  M. Ricketts,et al.  Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver , 2016, PloS one.

[4]  M. Ricketts,et al.  Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia. , 2016, Molecular nutrition & food research.

[5]  M. Ricketts,et al.  A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis , 2015, PloS one.

[6]  Peter Tontonoz,et al.  Liver X receptors in lipid metabolism: opportunities for drug discovery , 2014, Nature Reviews Drug Discovery.

[7]  B. O’Malley,et al.  Nuclear receptor coactivators: master regulators of human health and disease. , 2014, Annual review of medicine.

[8]  Hiram Beltrán-Sánchez,et al.  Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. , 2013, Journal of the American College of Cardiology.

[9]  L. Shi,et al.  Date fruit: chemical composition, nutritional and medicinal values, products. , 2013, Journal of the science of food and agriculture.

[10]  N. Osakabe,et al.  Health Beneficial Effects of Food Factors Can Be Applicable to Humans ? , 2013 .

[11]  Fei Li,et al.  FXR signaling in the enterohepatic system , 2013, Molecular and Cellular Endocrinology.

[12]  A. Caimari,et al.  Low doses of grape seed procyanidins reduce adiposity and improve the plasma lipid profile in hamsters , 2013, International Journal of Obesity.

[13]  Dr David Vauzour,et al.  Effect of cultivar type and ripening on the polyphenol content of date palm fruit. , 2013, Journal of agricultural and food chemistry.

[14]  Michael G. Sugiyama,et al.  The Ileal Lipid Binding Protein Is Required for Efficient Absorption and Transport of Bile Acids in the Distal Portion of the Murine Small Intestine , 2012, PloS one.

[15]  D. Shanmuganayagam,et al.  Deconvolution of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry isotope patterns to determine ratios of A-type to B-type interflavan bonds in cranberry proanthocyanidins. , 2012, Food chemistry.

[16]  M. Ricketts,et al.  Dietary modification of metabolic pathways via nuclear hormone receptors , 2012, Cell biochemistry and function.

[17]  F. Gonzalez.  Nuclear receptor control of enterohepatic circulation. , 2012, Comprehensive Physiology.

[18]  F. Sacks,et al.  Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. , 2012, The Journal of clinical endocrinology and metabolism.

[19]  D. Shanmuganayagam,et al.  Comparison of isolated cranberry (Vaccinium macrocarpon Ait.) proanthocyanidins to catechin and procyanidins A2 and B2 for use as standards in the 4-(dimethylamino)cinnamaldehyde assay. , 2012, Journal of agricultural and food chemistry.

[20]  P. Tontonoz,et al.  Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR , 2012, Nature Reviews Molecular Cell Biology.

[21]  Taosheng Chen,et al.  A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor. , 2012, Toxicology and applied pharmacology.

[22]  P. Vayalil.  Date Fruits (Phoenix dactylifera Linn): An Emerging Medicinal Food , 2012, Critical reviews in food science and nutrition.

[23]  J. Alkaabi,et al.  Glycemic indices of five varieties of dates in healthy and diabetic subjects , 2011, Nutrition journal.

[24]  D. Panagiotakos,et al.  The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. , 2011, Journal of the American College of Cardiology.

[25]  A. Moschetta,et al.  Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis. , 2010, Cell metabolism.

[26]  F. Gonzalez,et al.  Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice , 2010, Laboratory Investigation.

[27]  M. Aviram,et al.  Effects of date ( Phoenix dactylifera L., Medjool or Hallawi Variety) consumption by healthy subjects on serum glucose and lipid levels and on serum oxidative status: a pilot study. , 2009, Journal of agricultural and food chemistry.

[28]  D. Moore,et al.  Dietary procyanidins enhance transcriptional activity of bile acid-activated FXR in vitro and reduce triglyceridemia in vivo in a FXR-dependent manner. , 2009, Molecular nutrition & food research.

[29]  D. Moore,et al.  Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. , 2009, The Journal of nutrition.

[30]  A. Wojdyło,et al.  Effect of L-ascorbic acid, sugar, pectin and freeze-thaw treatment on polyphenol content of frozen strawberries , 2009 .

[31]  S. Strom,et al.  Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α‐hydroxylase gene expression , 2009, Hepatology.

[32]  Kaye Foster-Powell,et al.  International Tables of Glycemic Index and Glycemic Load Values: 2008 , 2008, Diabetes Care.

[33]  Chang Yong Lee,et al.  Nutritional and Functional Properties of Dates: A Review , 2008, Critical reviews in food science and nutrition.

[34]  D. Moore,et al.  Dietary procyanidins lower triglyceride levels signaling through the nuclear receptor small heterodimer partner. , 2008, Molecular nutrition & food research.

[35]  R. Domitrović,et al.  Dose- and Time-Dependent Effects of Luteolin on Liver Metallothioneins and Metals in Carbon Tetrachloride-Induced Hepatotoxicity in Mice , 2008, Biological Trace Element Research.

[36]  Michael K. Hansen,et al.  Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. , 2008, Current opinion in investigational drugs.

[37]  P. Edwards,et al.  FXR signaling in metabolic disease , 2008, FEBS letters.

[38]  S. Kliewer,et al.  Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine Published, JLR Papers in Press, August 24, 2007. , 2007, Journal of Lipid Research.

[39]  D. Moore,et al.  The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. , 2007, Molecular endocrinology.

[40]  J. A. Lombardi,et al.  Angiotensin-converting enzyme inhibition by Brazilian plants. , 2007, Fitoterapia.

[41]  J. Auwerx,et al.  In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. , 2007, Molecular endocrinology.

[42]  Jiang He,et al.  Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. , 2006, The American journal of medicine.

[43]  P. Mattila,et al.  Phenolic acids in berries, fruits, and beverages. , 2006, Journal of agricultural and food chemistry.

[44]  F. Tomás-Barberán,et al.  The flavonoid glycosides and procyanidin composition of Deglet Noor dates (Phoenix dactylifera). , 2006, Journal of agricultural and food chemistry.

[45]  S. Vavricka,et al.  The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-α and -β genes , 2006 .

[46]  D. Mangelsdorf,et al.  LXRS and FXR: the yin and yang of cholesterol and fat metabolism. , 2006, Annual review of physiology.

[47]  N. Hosten,et al.  Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging , 2005, Alimentary pharmacology & therapeutics.

[48]  S. Kliewer,et al.  Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. , 2005, Cell metabolism.

[49]  F. Shahidi,et al.  Compositional and sensory characteristics of three native sun-dried date (Phoenix dactylifera L.) varieties grown in Oman. , 2005, Journal of agricultural and food chemistry.

[50]  C. Krueger,et al.  MALDI-TOF mass spectrometry of oligomeric food polyphenols. , 2005, Phytochemistry.

[51]  F. Shahidi,et al.  Comparison of antioxidant activity, anthocyanins, carotenoids, and phenolics of three native fresh and sun-dried date (Phoenix dactylifera L.) varieties grown in Oman. , 2005, Journal of agricultural and food chemistry.

[52]  Tosca L. Zern,et al.  Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. , 2005, The Journal of nutrition.

[53]  V. Menon,et al.  Ferulic acid, a natural protector against carbon tetrachloride‐induced toxicity , 2005, Fundamental & clinical pharmacology.

[54]  D. Moore,et al.  Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. A review. , 2005, The Journal of nutritional biochemistry.

[55]  P. Dawson,et al.  The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter* , 2005, Journal of Biological Chemistry.

[56]  H. Frederiksen,et al.  Dietary proanthocyanidins: occurrence, dietary intake, bioavailability, and protection against cardiovascular disease. , 2005, Molecular nutrition & food research.

[57]  Gang Li,et al.  Mechanisms of apigenin-7-glucoside as a hepatoprotective agent. , 2005, Biomedical and environmental sciences : BES.

[58]  P. Kefalas,et al.  Phenolic profile and antioxidant activity of the Algerian ripe date palm fruit (Phoenix dactylifera) , 2005 .

[59]  A. Gutiérrez,et al.  Identification of intact long-chain p-hydroxycinnamate esters in leaf fibers of abaca (Musa textilis) using gas chromatography/mass spectrometry. , 2004, Rapid communications in mass spectrometry : RCM.

[60]  V. Ossipov,et al.  Analysis of procyanidins in pine bark with reversed-phase and normal-phase high-performance liquid chromatography–electrospray ionization mass spectrometry , 2004 .

[61]  C. Auger,et al.  Phenolics from commercialized grape extracts prevent early atherosclerotic lesions in hamsters by mechanisms other than antioxidant effect. , 2004, Journal of agricultural and food chemistry.

[62]  Sander M Houten,et al.  Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. , 2004, The Journal of clinical investigation.

[63]  F. Kuipers,et al.  Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient Mice , 2003, Journal of Biological Chemistry.

[64]  P. Dawson,et al.  Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic Cycling of Bile Acids in Mice* , 2003, Journal of Biological Chemistry.

[65]  S. Kliewer,et al.  Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. , 2003, Genes & development.

[66]  B. Shneider,et al.  Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. , 2003, Hepatology.

[67]  Prozorovskaia Nn,et al.  Antioxidant properties of a leaf extract from Aronia (Aronia melanocarba) containing proanthocyanidins , 2003 .

[68]  Jasmine Chen,et al.  Identification of Gene-selective Modulators of the Bile Acid Receptor FXR* , 2003, The Journal of Biological Chemistry.

[69]  C. Krueger,et al.  Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of heteropolyflavan-3-ols and glucosylated heteropolyflavans in sorghum [Sorghum bicolor (L.) Moench]. , 2003, Journal of agricultural and food chemistry.

[70]  Richard J. Marshall,et al.  The fruit of the date palm: its possible use as the best food for the future? , 2003, International journal of food sciences and nutrition.

[71]  D. Moore,et al.  Bile acids regulate the ontogenic expression of ileal bile acid binding protein in the rat via the farnesoid X receptor. , 2002, Gastroenterology.

[72]  D. Mangelsdorf,et al.  A Natural Product That Lowers Cholesterol As an Antagonist Ligand for FXR , 2002, Science.

[73]  R. Evans,et al.  Nuclear receptors and lipid physiology: opening the X-files. , 2001, Science.

[74]  D. Wiebe,et al.  Cranberry proanthocyanidins associate with low-density lipoprotein and inhibit in vitro Cu2+-induced oxidation† , 2001 .

[75]  M. Makishima,et al.  Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid Receptor* , 2001, The Journal of Biological Chemistry.

[76]  T. A. Kerr,et al.  Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. , 2000, Molecular cell.

[77]  B. Neuschwander‐Tetri,et al.  Humanized xenobiotic response in mice expressing nuclear receptor SXR , 2000, Nature.

[78]  J. Folts,et al.  Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of polygalloyl polyflavan-3-ols in grape seed extract. , 2000, Journal of agricultural and food chemistry.

[79]  T. Willson,et al.  Identification of a Bile Acid-responsive Element in the Human Ileal Bile Acid-binding Protein Gene , 1999, The Journal of Biological Chemistry.

[80]  A. Goddard,et al.  FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. , 1999, Cytokine.

[81]  D. Russell,et al.  Nuclear Orphan Receptors Control Cholesterol Catabolism , 1999, Cell.

[82]  J. Lehmann,et al.  Bile acids: natural ligands for an orphan nuclear receptor. , 1999, Science.

[83]  M. Makishima,et al.  Identification of a nuclear receptor for bile acids. , 1999, Science.

[84]  Jasmine Chen,et al.  Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. , 1999, Molecular cell.

[85]  J. Lehmann,et al.  Activation of the orphan receptor RIP14 by retinoids. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[86]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[87]  D Kromhout,et al.  Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. , 1995, Archives of internal medicine.

[88]  E. Feskens,et al.  Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study , 1993, The Lancet.

[89]  P. V. Soest,et al.  Condensed tannins: A factor limiting the use of cassava forage , 1982 .

[90]  T. Wolever,et al.  Glycemic index of foods: a physiological basis for carbohydrate exchange. , 1981, The American journal of clinical nutrition.

[91]  Polly,et al.  Critical Reviews in Food Science and Nutrition , 2011 .

[92]  S. Vavricka,et al.  The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[93]  B. M. Forman,et al.  FXR-activatingg ligands inhibit rabbit ASBT expression viaa FXR-SHP-FTF cascade , 2007 .

[94]  P. Dawson,et al.  The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. , 2005, The Journal of biological chemistry.

[95]  C. Krueger,et al.  Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry of anthocyanin-polyflavan-3-ol oligomers in cranberry fruit (Vaccinium macrocarpon, Ait.) and spray-dried cranberry juice , 2004 .

[96]  O. Ipatova,et al.  [Antioxidant properties of a leaf extract from Aronia (Aronia melanocarba) containing proanthocyanidins]. , 2003, Biomeditsinskaia khimiia.

[97]  A. Anisfeld,et al.  BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. , 2002, Journal of lipid research.

[98]  L. Moore,et al.  The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. , 2000, Molecular endocrinology.