New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.
Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases.
Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands. Electronic address: u.h.beuers@amc.uva.nl.
Ulrich
U
Beuers
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
Michael
M
Trauner
Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands.
Peter
P
Jansen
UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, F-75012 Paris, France.
Raoul
R
Poupon
D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy*; D006801:Humans; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors; D047493:PPAR alpha / Q000819:agonists; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol / Q000819:agonists; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D011987:Receptors, Steroid / Q000819:agonists*; D027981:Symporters / Q000037:antagonists & inhibitors; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use; D000099150:Receptor, Farnesoid X-Activated
D029363:Organic Anion Transporters, Sodium-Dependent; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; D027981:Symporters; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human; C071908:sodium-bile acid cotransporter
Cholestasis; FXR; PXR; UDCA