title: Targeting FXR in cholestasis: hype or hope.
abstract: BACKGROUND
  Bile acids, the end product of cholesterol metabolism, are signaling molecules. The farnesoid X receptor (FXR) is a bile acid sensor and is part of a network of nuclear receptors that regulate bile acid homeostasis. In addition to FXR, bile acids activate other nuclear receptors (CAR, PXR and VDR), cell surface receptors including the G protein-coupled bile acid receptor 1 (GP-BAR1/TGR5), muscarinic receptor and calcium-gated potassium channels.
  
  
  METHODS
  The semisynthetic bile acid derivative 6-ethyl chenodeoxycholic acid (6-ECDCA, INT-747 later christened obeticholic acid) is a dual FXR/GP-BAR1 ligand that attenuates bile flow impairment in cholestasis induced by 17β-estradiol; a model of pregnancy-induced cholestasis. Phase II trials with this agent in early stage primary biliary cirrhosis have shown beneficial effects on surrogate markers of damage progression, specifically alkaline phosphatase, with a dose-dependent itching being the most severe and common side effect (up to 70% of patients) leading to therapy discontinuation in 38% of patients. GP-BAR1 activation in the skin triggers itching, thus providing a molecular explanation for this side effect.
  
  
  CONCLUSIONS
  While the role of FXR activation in treating severe cholestasis needs confirmation, the activation of GP-BAR1 is likely involved in pruritus development that associates with clinical use of dual FXR/GP-BAR1 ligands. FXR antagonist could be an interesting opportunity for treatment of severe/obstructive cholestasis.
authors.affiliation: University of Perugia, Dipartimento di Scienze Chirurgiche e Biomediche, Sezione di Gastroenterologia, Nuova Facoltà di Medicina e Chirurgia , Edificio B, Piano III, Piazzale L. Severi, 1, 06132 S. Andrea delle Fratte, Perugia , Italy stefano.fiorucci@unipg.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ricci
authors.forename: Vittorio
authors.initials: V
authors.lastname: Giuliano
authors.forename: Annibale
authors.initials: A
authors.lastname: Donini
authors.forename: Franco
authors.initials: F
authors.lastname: Baldelli
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000378:metabolism; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism*; D002986:Clinical Trials as Topic / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: G protein-coupled bile acid receptor 1; cholestasis; farnesoid X receptor; muscarinic receptors; voltage-calcium-gated potassium channels