Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

作者：Rian M. Nijmeijer, Raffaella Maria Gadaleta, Saskia W. C. van Mil, Adriaan A. van Bodegraven, J. Bart A. Crusius, Gerard D. H. Dijkstra, Daan W. Hommes, Dirk J. de Jong, Pieter C F Stokkers, Hein W. Verspaget, Rinse Karel Weersma, C. Janneke van der Woude, Janneke M. Stapelbroek, Marguerite E I Schipper, Cisca Wijmenga, Karel J. van Erpecum, Bas Oldenburg, on behalf of the Dutch Initiative on Crohn, Colitis (ICC) · 发表于：PLoS ONE · 年份：2011 · DOI：10.1371/journal.pone.0023745 · 被引用次数：117 · 研究领域：Drug Transport and Resistance Mechanisms、Inflammatory Bowel Disease、Protein Kinase Regulation and GTPase Signaling

BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNP...