We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Loss of Hepatocyte-Nuclear-Factor-4a Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice.
- Authors
Darsigny, Mathieu; Babeu, Jean-Philippe; Dupuis, Andrée-Anne; Furth, Emma E.; Seidman, Ernest G.; Lévy, É mile; Verdu, Elena F.; Gendron, Fernand-Pierre; Boudreau, François
- Abstract
Background: Hnf4α, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4α in the maintenance of gut inflammatory homeostasis in mice. Methodology/Principal Findings: We show here that specific epithelial deletion of Hnf4a in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4a null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4a mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4α gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. Conclusion: Our results highlight the critical role of Hnf4α to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4α in the regulation of claudin-15 expression. This establishes Hnf4α as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.
- Subjects
HEPATOCYTE growth factor; INTESTINAL diseases; INFLAMMATION; COLITIS; HOMEOSTASIS; CYTOKINES; CHEMOKINES; SECRETION; GENES
- Publication
PLoS ONE, 2009, Vol 4, Issue 10, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0007609