title: Enteroendocrine cells are a potential source of serum autotaxin in men.
abstract: Serum autotaxin (ATX) activity is significantly increased in cholestatic patients. Our study aimed to unravel the source(s) of ATX in cholestasis.
  
  
  
  ATX activity and protein were measured in sera of healthy (n=33) and cholestatic patients (n=152), including women with intrahepatic cholestasis of pregnancy. ATX mRNA and protein expression were analyzed in various tissues from mice and men. Induction of ATX activity was assessed in mouse models of extrahepatic (bile duct ligation) and intrahepatic cholestasis (Atp8b1(G308V/G308V), 0.1% cholate-supplemented diet). ATX clearance in cholestatic and control mice was assessed after intravenous injection of recombinant ATX. Human hepatic clearance was estimated by comparing ATX activity in portal and hepatic vein serum.
  
  
  
  Serum ATX activity and ATX protein concentration tightly correlated under all conditions in patients and controls (p<0.0001). In humans Atx mRNA was highly expressed in small intestine, whereas in mice Atx was expressed mainly in brain and placenta but not in small intestine. Extensive ATX protein expression was identified in human, but not murine intestinal enteroendocrine cells. In murine models of cholestasis and cholestatic pregnancy plasma ATX activity was only mildly elevated (up to 2.1-fold). Atx tissue expression and rATX clearance after parenteral administration did not differ between cholestatic and control mice.
  
  
  
  Serum ATX activity during cholestasis and itch is enhanced by increased protein concentration rather than enzymatic induction. In mice, clearance of ATX is not affected by cholestasis. Small intestinal ATX expression by enteroendocrine cells might represent an important source of cholestasis-induced serum ATX activity in men.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bolier
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Tolenaars
authors.affiliation: Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Job
authors.initials: J
authors.lastname: Saris
authors.affiliation: Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Department of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Parés
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Piter J
authors.initials: PJ
authors.lastname: Bosma
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: r.p.oude-elferink@amc.uva.nl.
authors.forename: Ronald P J
authors.initials: RPJ
authors.lastname: Oude Elferink
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000097:blood* / Q000201:enzymology / Q000473:pathology; D019858:Enteroendocrine Cells / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000097:blood*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D012333:RNA, Messenger; D000099189:Lysophospholipase D
keywords: Autotaxin; Cholestasis; Enteroendocrine cells; Itch; Pruritus