title: Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease.
abstract: BACKGROUND
  Hepatocyte nuclear factor 4alpha (HNF4alpha; NR2A1) is an orphan member of the nuclear receptor superfamily expressed in liver and intestine. While HNF4alpha 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 HNF4alpha and other nuclear receptors. An intestine-specific HNF4alpha null mouse line (Hnf4alpha(DeltaIEpC)) was generated using an Hnf4alpha-floxed allele and villin-Cre transgene. These mice and their control floxed counterparts (Hnf4alpha(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, HNF4alpha was significantly decreased in intestinal tissues from Crohn's disease and ulcerative colitis patients. HNF4alpha expression was also suppressed in the intestine of DSS-treated mice. In Hnf4alpha(DeltaIEpC) mice, disruption of HNF4alpha expression was observed in the epithelial cells throughout the intestine. In the DSS-induced colitis model Hnf4alpha(DeltaIEpC) 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 Hnf4alpha(F/F) mice. Furthermore, the Hnf4alpha(DeltaIEpC) 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 HNF4alpha does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Junko
authors.initials: J
authors.lastname: Inoue
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.forename: Sunhee
authors.initials: S
authors.lastname: Yim
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.forename: Reiko
authors.initials: R
authors.lastname: Kurotani
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D020346:Aquaporins / Q000032:analysis; D015152:Blotting, Northern; D015153:Blotting, Western; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000737:chemistry; D003424:Crohn Disease / Q000378:metabolism; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000378:metabolism; D007422:Intestines / Q000737:chemistry*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009077:Mucins / Q000032:analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis; D008625:Tiopronin / Q000032:analysis
chemical_list: D020346:Aquaporins; D051557:Hepatocyte Nuclear Factor 4; D009077:Mucins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D008625:Tiopronin