title: Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis.
abstract: BACKGROUND
  Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis.
  
  
  METHODS
  Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs.
  
  
  RESULTS
  In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology.
  
  
  CONCLUSIONS
  We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rian M
authors.initials: RM
authors.lastname: Nijmeijer
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands; Department of General Surgery, Maastricht University, Maastricht, The Netherlands.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Schaap
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Alexander J J
authors.initials: AJ
authors.lastname: Smits
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands; Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Louis M A
authors.initials: LM
authors.lastname: Akkermans
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands; Neurotoxicology Research Group, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Alfons B A
authors.initials: AB
authors.lastname: Kroese
authors.affiliation: Department of Operating Rooms, University Medical Center St. Radboud, Nijmegen, the Netherlands; Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Ger T
authors.initials: GT
authors.lastname: Rijkers
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marguerite E I
authors.initials: ME
authors.lastname: Schipper
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: André
authors.initials: A
authors.lastname: Verheem
authors.affiliation: Department of Genetics, University Medical Centrum Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Operating Rooms, University Medical Center St. Radboud, Nijmegen, the Netherlands.
authors.forename: Hein G
authors.initials: HG
authors.lastname: Gooszen
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Karel J
authors.initials: KJ
authors.lastname: van Erpecum
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D017097:Electric Impedance; D005346:Fibroblast Growth Factors / Q000097:blood; D055786:Gene Knockout Techniques; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007413:Intestinal Mucosa / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human