1. Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis
- Author
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Nijmeijer, Rian M, Schaap, Frank G, Smits, Alexander J J, Kremer, Andreas E, Akkermans, Louis M A, Kroese, A.B., Rijkers, Ger T, Schipper, Marguerite E I, Verheem, André, Wijmenga, Cisca, Gooszen, Hein G, van Erpecum, Karel J, Dep IRAS, Sub IRAS Tox CMT/NTX, Risk Assessment of Toxic and Immunomodulatory Agents, IRAS RATIA1, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Surgery, RS: NUTRIM - R2 - Gut-liver homeostasis, Other departments, Dep IRAS, Sub IRAS Tox CMT/NTX, Risk Assessment of Toxic and Immunomodulatory Agents, and IRAS RATIA1
- Subjects
Male ,Gene Expression ,Receptors, Cytoplasmic and Nuclear ,Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14] ,Gene Knockout Techniques ,Medizinische Fakultät ,GROWTH-FACTOR 19 ,Medicine and Health Sciences ,Electric Impedance ,Intestinal Mucosa ,Receptor ,Mice, Knockout ,Multidisciplinary ,Pancreatitis, Acute Necrotizing ,EXOCRINE PANCREAS ,Animal Models ,NUCLEAR RECEPTOR FXR ,INTESTINAL BARRIER DYSFUNCTION ,Acute pancreatitis ,Medicine ,medicine.symptom ,Anatomy ,ORGAN FAILURE ,Research Article ,EXPRESSION ,medicine.medical_specialty ,Science ,Inflammation ,Endocrine System ,Mouse Models ,Gastroenterology and Hepatology ,Biology ,BINDING PROTEIN ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Model Organisms ,Ileum ,Internal medicine ,medicine ,Genetics ,Animals ,Humans ,ddc:610 ,Pancreas ,Genetic Association Studies ,FGF15 ,Biology and Life Sciences ,FGF19 ,Human Genetics ,medicine.disease ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,MICE ,Endocrinology ,GALLSTONE DISEASE ,Nuclear receptor ,Pancreatitis ,Case-Control Studies ,Genetics of Disease ,BILE ,Farnesoid X receptor ,Gene Function - Abstract
Contains fulltext : 170664.PDF (Publisher’s version ) (Open Access) 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-kappaB 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. CONCLUSION: 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.
- Published
- 2014