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

Abstract

BackgroundHnf4α, 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 FindingsWe show here that specific epithelial deletion of Hnf4α 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 Hnf4α 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 Hnf4α 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.ConclusionOur 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.

Modification in Oxidative Stress, Inflammation, and Lipoprotein Assembly in Response to Hepatocyte Nuclear Factor 4α Knockdown in Intestinal Epithelial Cells

“…The data of this study are in line with recent studies that reported the protective action of HNF4␣ against inflammatory bowel diseases (26,64). Moreover, the potential associations between the HNF4A locus and ulcerative colitis (105) strengthen the potent influence of this multifaceted transcription factor on the anti-inflammatory defense.…”

“…Furthermore, the intestine-specific HNF4␣ knock-out mouse line demonstrated an amplified susceptibility to dextran sulfate sodium-induced colitis, and consistent with our data, several cytokines were significantly increased (26). Moreover, a long term and chronic inflammatory consequence arising from the colonic epithelial loss of this transcriptional regulator was observed in the intestine of HNF4␣ knock-out mice (64). Finally, a cross-talk between HNF4␣ and NF-B was reported (65)(66)(67).…”

Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice

“…Also, the apparent linkage between the intestinal ontogenic program of fat-1 mice and the decrease in intestinal HNF-4 ␣ activity may indicate that suppression of HNF-4 ␣ transcriptional activity may alleviate CRC. These predictions seem to be corroborated by the following reported fi ndings: i ) HNF-4 ␣ transcript and protein levels increased 2-to 3-fold in human CRC samples compared with their paired margin resections ( 50 ); ii ) silencing HNF-4 ␣ expression of HT29 CRC cells by SiHNF-4 ␣ resulted in suppressing their proliferation and in activating E-cadherin expression ( 9 ); iii ) LCFA analogs of the MEDICA series that act as HNF-4 ␣ ligand antagonists inhibited proliferation of HT29 and Caco2 CRC cells and suppressed growth of HT29 CRC xenografts ( 9 ); and iv ) postnatal HNF-4 ␣ conditional deletion resulted in robust decrease in polyp multiplicity in Apc Min mice ( 50 ). Altogether, these fi ndings may indicate that suppression of intestinal HNF-4 ␣ activity by (n-3) PUFA may ameliorate diabesity-induced intestinal ontogenesis and offer an effective modality for preventing the development of CRC.…”

Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

“…Remarkably, APOA1, APOA4, and APOC3 reside in close proximity on chromosome 11 and were all downregulated within the APOA1 gene coexpression signature, suggesting regulation by common transcriptional factors. Indeed, HNF4α and HNF4γ binding has been described within the APOA1/A4/C3 chromosomal region (Supplemental Figure 10), and intestinal epithelial cell-specific deletion of Hnf4a leads to spontaneous intestinal inflammation in mice (37).This substantial suppression of the antioxidant lipoproteins in CD can hence serve as a potential target for future therapies, whereby supplementing the apolipoprotein axis could be beneficial to reverse some of the CD-specific pathogenesis in the ileum.…”