4.6 Article

Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice

Journal

PLOS ONE
Volume 4, Issue 10, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0007609

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Funding

  1. Canadian Institutes of Health Research [CTP-82942, MOP-897702] Funding Source: Medline

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Background: Hnf4 alpha, 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 Hnf4 alpha in the maintenance of gut inflammatory homeostasis in mice. Methodology/Principal Findings: We show here that specific epithelial deletion of Hnf4 alpha 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 Hnf4 alpha 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 Hnf4 alpha 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 Hnf4 alpha 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 Hnf4 alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4 alpha in the regulation of claudin-15 expression. This establishes Hnf4 alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.

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