title: Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice.
abstract: The etiopathogenesis of primary sclerosing cholangitis is unknown. Genetic variants of fucosyltransferase 2 (FUT2) have been identified in genome-wide association studies as risk factors for primary sclerosing cholangitis. We investigated the role of Fut2 in murine liver pathophysiology by studying Fut2-/-mice. Fut2-/-mice were viable and fertile, had lower body weight than wild-type (wt) littermates and gray fur. Half of the Fut2-/-mice showed serum bile salt levels 40 times higher than wt (Fut2-/-high), whereas the remainder were normocholanemic (Fut2-/-low). Fut2-/-mice showed normal serum liver tests, bile flow, biliary bile salt secretion, fecal bile salt loss, and expression of major hepatocellular bile salt transporters and cytochrome P450 7a1, the key regulator of bile salt synthesis, indicating that elevated serum bile salts in Fut2-/-highmice were not explained by cholestasis. Fut2-/-highmice, but not Fut2-/-lowmice, were sensitive to hydrophobic bile salt feeding (0.3% glycochenodeoxycholate); they rapidly lost weight and showed elevation of serum liver tests (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase) and areas of liver parenchymal necrosis. Histomorphological evaluation revealed the presence of paraportal shunting vessels, increased numbers of portal vascular structures, wall thickening of some portal arteries, and periductal fibrosis in Fut2-/-highmice more than Fut2-/-lowmice and not wt mice. Unconjugated bilirubin and ammonia were or tended to be elevated in Fut2-/-highmice only. Portosystemic shunting was demonstrated by portal angiography, which disclosed virtually complete portosystemic shunting in Fut2-/-highmice, discrete portosystemic shunting in Fut2-/-lowmice, and no shunting in wt littermates.
  
  
  
  Liver pathology in Fut2-/-mice is dominated by consequences of portosystemic shunting resulting in microcirculatory disturbances, mild (secondary) periductal fibrosis, and sensitivity toward human bile salt toxicity. (Hepatology 2017;66:542-554).
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Maroni
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Medicine II, University of Munich (LMU), Munich, Germany.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Hohenester
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Stan F J
authors.initials: SFJ
authors.lastname: van de Graaf
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Tolenaars
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Krijn
authors.initials: K
authors.lastname: van Lienden
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald P J
authors.initials: RPJ
authors.lastname: Oude Elferink
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001707:Biopsy, Needle; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005647:Fucosyltransferases / Q000235:genetics*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011167:Portacaval Shunt, Surgical; D011168:Portal System / Q000473:pathology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018570:Risk Assessment; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D001647:Bile Acids and Salts; D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase