Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis

Journal article


Publication Details

Author(s): Nijmeijer RM, Schaap FG, Smits AJJ, Kremer A, Akkermans LMA, Kroese ABA, Rijkers GT, Schipper MEI, Verheem A, Wijmenga C, Gooszen HG, Van Erpecum KJ
Journal: PLoS ONE
Publication year: 2014
Volume: 9
Journal issue: 12
Pages range: e114393
ISSN: 1932-6203


Abstract


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-?B 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.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.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.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.



FAU Authors / FAU Editors

Kremer, Andreas PD Dr.
Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie


External institutions with authors

Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC)
University Medical Centre Utrecht (UMC Utrecht)
University of Amsterdam
University of Groningen / Rijksuniversiteit Groningen


How to cite

APA:
Nijmeijer, R.M., Schaap, F.G., Smits, A.J.J., Kremer, A., Akkermans, L.M.A., Kroese, A.B.A.,... Van Erpecum, K.J. (2014). Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis. PLoS ONE, 9(12), e114393. https://dx.doi.org/10.1371/journal.pone.0114393

MLA:
Nijmeijer, Rian M., et al. "Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis." PLoS ONE 9.12 (2014): e114393.

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Last updated on 2018-10-10 at 08:22