title: Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity.
abstract: OBJECTIVE
  Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients.
  
  
  METHODS
  In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery.
  
  
  RESULTS
  Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid.
  
  
  CONCLUSIONS
  These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT.
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Karolinska Institutet, Department of Clinical Science at Danderyds Hospital, Stockholm, Sweden; Department of Surgery, Ersta Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thorell
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Pooja
authors.initials: P
authors.lastname: Jha
authors.affiliation: Core Facility for Mass Spectrometry, Medical University of Graz, Graz, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Koefeler
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hoesel
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Fauler
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stojakovic
authors.affiliation: Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Curt
authors.initials: C
authors.lastname: Einarsson
authors.affiliation: Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: hanns-ulrich.marschall@gu.se.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism; D009767:Obesity, Morbid / Q000188:drug therapy* / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D019301:Oleic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C523776:SCD1 protein, human
keywords: 3-hydroxy-3-methylglutaryl-CoA reductase; FGF19; Lipogenesis; Non-alcoholic fatty liver disease; Stearoyl-CoA desaturase