Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.
BACKGROUND
Hnf4alpha, 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 Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice.


RESULTS
We show here that specific epithelial deletion of Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease.


CONCLUSIONS
Our results highlight the critical role of Hnf4alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4alpha in the regulation of claudin-15 expression. This establishes Hnf4alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.
Darsigny
Mathieu
M
Canadian Institutes of Health Research Team on Digestive Epithelium, Département d'Anatomie et Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Babeu
Jean-Philippe
JP
Dupuis
Andrée-Anne
AA
Furth
Emma E
EE
Seidman
Ernest G
EG
Lévy
Emile
E
Verdu
Elena F
EF
Gendron
Fernand-Pierre
FP
Boudreau
François
F
D000818:Animals; D057167:Claudins; D003092:Colitis / Q000139:chemically induced*; D003106:Colon / Q000378:metabolism*; D017353:Gene Deletion; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006706:Homeostasis; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D017136:Ion Transport; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
D057167:Claudins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D008565:Membrane Proteins; C459596:claudin 15