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Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.

ABSTRACT: 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 SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.

SUBMITTER: Nijmeijer RM

PROVIDER: S-EPMC3161760 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.

Nijmeijer Rian M RM Gadaleta Raffaella M RM van Mil Saskia W C SW van Bodegraven Adriaan A AA Crusius J Bart A JB Dijkstra Gerard G Hommes Daan W DW de Jong Dirk J DJ Stokkers Pieter C F PC Verspaget Hein W HW Weersma Rinse K RK van der Woude C Janneke CJ Stapelbroek Janneke M JM Schipper Marguerite E I ME Wijmenga Cisca C van Erpecum Karel J KJ Oldenburg Bas B

PloS one 20110822 8

<h4>Background</h4>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.<h4>Methods</h4>mRNA expression of FXR and F ...[more]

PMID: 21887309

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Project description:BackgroundSmall ubiquitin-like modifiers (SUMO) are covalently conjugated to other proteins including nuclear receptors leading to modification of various cellular processes.ResultsLigand-dependent SUMOylation of farnesoid X receptor (FXR) negatively regulates the expression of its target genes.ConclusionSUMO modification attenuates the capacity of FXR to function as a transcriptional activator.SignificanceDefining post-translation modification of FXR bySUMOis important to understanding how this nuclear receptor functions in health and disease. The farnesoid X receptor (FXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metabolism including bile acid homeostasis. Here we show that FXR is covalently modified by the small ubiquitin-like modifier (Sumo1), an important regulator of cell signaling and transcription. Well conserved consensus sites at lysine 122 and 275 in the AF-1 and ligand binding domains, respectively, of FXR were subject to SUMOylation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analysis showed that Sumo1 was recruited to the bile salt export pump (BSEP), the small heterodimer partner (SHP), and the OSTα-OSTβ organic solute transporter loci in a ligand-dependent fashion. Sequential chromatin immunoprecipitation (ChIP-ReChIP) verified the concurrent binding of FXR and Sumo1 to the BSEP and SHP promoters. Overexpression of Sumo1 markedly decreased binding and/or recruitment of FXR to the BSEP and SHP promoters on ChIP-ReChIP. SUMOylation did not have an apparent effect on nuclear localization of FXR. Expression of Sumo1 markedly inhibited the ligand-dependent, transactivation of BSEP and SHP promoters by FXR/retinoid X receptor α (RXRα) in HepG2 cells. In contrast, mutations that abolished SUMOylation of FXR or siRNA knockdown of Sumo1 expression augmented the transactivation of BSEP and SHP promoters by FXR. Pathways for SUMOylation were significantly altered during obstructive cholestasis with differential Sumo1 recruitment to the promoters of FXR target genes. In conclusion, FXR is subject to SUMOylation that regulates its capacity to transactivate its target genes in normal liver and during obstructive cholestasis.

Dataset Information

Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.

Publications

Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.

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