Hepatocyte nuclear factor 4α in the intestinal epithelial cells protects against inflammatory bowel disease

Background: Hepatocyte nuclear factor 4 alpha (HNF4 alpha; NR2Al) is an orphan member of the nuclear receptor superfamily expressed in liver and intestine. While HNF4 alpha expression is critical for liver function, its role in the gut and in the pathogenesis of inflammatory bowel disease (IBD) is unknown. Methods: Human intestinal biopsies from control and IBD patients were examined for expression of mRNAs encoding HNF4 alpha and other nuclear receptors. An intestine-specific HNF4a null mouse line (Hnf4 alpha(Delta IEpC)) was generated using an Hnf4 alpha-floxed allele and villin-Cre transgene. These mice and their control floxed counter-parts (Hnf4 alpha(F/F)), were subjected to a dextran sulfate sodium (DSS)-induced IBD colitis protocol and their clinical symptoms and gene expression patterns determined. Results: In human intestinal biopsies, HNF4 alpha was significantly decreased in intestinal tissues from Crohn's disease and ulcerative colitis patients. HNF4 alpha expression was also suppressed in the intestine of DSS-treated mice. In Hnf4 alpha(Delta IEpC) mice, disruption of HNF4 alpha expression was observed in the epithelial cells throughout the intestine. In the DSS-induced colitis model Hnf4 alpha(Delta IEpC) mice showed markedly more severe changes in clinical symptoms and pathologies associated with IBD including loss of body weight, colon length, and histological morphology as compared with Hnf4 alpha(F/F) mice. Furthermore, the Hnf4 alpha(Delta IEpC) mice demonstrate a significant alteration of mucin-associated genes and increased intestinal permeability, which may play an important role in the increased susceptibility to acute colitis following an inflammatory insult. Conclusions: While HNF4 alpha does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis.