title: Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets.
abstract: Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6α-ethyl-chenodeoxycholic acid, modulate platelet activation nongenomically.
  
  
  
  FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR.
  
  
  
  This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease.
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.|Department of Physiology & NUS Immunology Program, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Moraes
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Unsworth
authors.affiliation: School of Pharmacy, University of Reading, Reading, Berkshire, RG6 6UB, UK.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Vaiyapuri
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Marfoua S
authors.initials: MS
authors.lastname: Ali
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Parvathy
authors.initials: P
authors.lastname: Sasikumar
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Sage
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Gagan D
authors.initials: GD
authors.lastname: Flora
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Bye
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Neline
authors.initials: N
authors.lastname: Kriek
authors.affiliation: European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dorchies
authors.affiliation: European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Molendi-Coste
authors.affiliation: European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.affiliation: European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 OTU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D005838:Genotype; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008024:Ligands; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000097:blood / Q000172:deficiency / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013997:Time Factors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D006152:Cyclic GMP; D005340:Fibrinogen; D007555:Isoxazoles; D008024:Ligands; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid; C412815:GW 4064
keywords: blood platelets; farnesoid X–activated receptor; fibrinogen; signal transduction; transcription factors