Targeting FXR in cholestasis: hype or hope. (December 2014)

• Record Type: Journal Article
• Authors: Fiorucci, Stefano; Distrutti, Eleonora; Ricci, Patrizia; Giuliano, Vittorio; Donini, Annibale; Baldelli, Franco
• Is Part Of: Expert opinion on therapeutic targets. Volume 18:Number 12(2014:Dec.)
• Page Start: 1449
• Page End: 1459
• Publication Date: 2014-12
• Subjects: Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1517/14728222.2014.956087
• Languages: English
• ISSNs: 1744-7631

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Introduction:</italic> </bold> 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.</p> <p> <bold> <italic>Areas covered:</italic> </bold> 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.</p> <p> <bold> <italic>Expert opinion:</italic> </bold> 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.</p> </abstract>