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Role of HNF4alpha in the adult colon

ABSTRACT: Background & Aims: HNF4α is an important transcriptional regulator of hepatocyte and pancreatic function. Hnf4α deletion is embryonically lethal with severe defects in visceral endoderm formation, liver maturation and colon development. However, the precise role of this transcription factor in maintaining homeostasis of the adult intestine remains unclear. Herein, we aimed to elucidate the adult intestinal functions of Hnf4α. Methods: A conditional intestinal epithelial Hnf4α knockout mouse was generated. Histological abnormality of the colonic mucosa was assessed by immunodetection and Western. Changes in global gene expression and biological network were analyzed. Results: Hnf4α intestine null mice developed normally until reaching young adulthood. Crypt distortion became apparent in the Hnf4α null colon at 3 months of age followed by focal areas of crypt dropout, increased immune cell infiltrates, crypt hyperplasia and early signs of polyposis later in life. A gene profiling analysis identified cell death and cell cycle related to cancer as the most significant sets of genes altered in the Hnf4α colon null mice. Expression levels of the tight junction proteins claudin 4, 8 and 15 were altered early in the colon epithelium of Hnf4α mutants and correlated with increased barrier permeability to a molecular tracer that does not normally penetrate normal mucosa. Conclusion: These observations support a functional role for Hnf4α in protecting the colonic mucosa against the initiation of the changes resembling inflammatory bowel diseases and polyp formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE11759 | GEO | 2008/12/01

SECONDARY ACCESSION(S): PRJNA106055

REPOSITORIES: GEO

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Project description:Background & Aims: HNF4Î± is an important transcriptional regulator of hepatocyte and pancreatic function. Hnf4Î± deletion is embryonically lethal with severe defects in visceral endoderm formation, liver maturation and colon development. However, the precise role of this transcription factor in maintaining homeostasis of the adult intestine remains unclear. Herein, we aimed to elucidate the adult intestinal functions of Hnf4Î±. Methods: A conditional intestinal epithelial Hnf4Î± knockout mouse was generated. Histological abnormality of the colonic mucosa was assessed by immunodetection and Western. Changes in global gene expression and biological network were analyzed. Results: Hnf4Î± intestine null mice developed normally until reaching young adulthood. Crypt distortion became apparent in the Hnf4Î± null colon at 3 months of age followed by focal areas of crypt dropout, increased immune cell infiltrates, crypt hyperplasia and early signs of polyposis later in life. A gene profiling analysis identified cell death and cell cycle related to cancer as the most significant sets of genes altered in the Hnf4Î± colon null mice. Expression levels of the tight junction proteins claudin 4, 8 and 15 were altered early in the colon epithelium of Hnf4Î± mutants and correlated with increased barrier permeability to a molecular tracer that does not normally penetrate normal mucosa. Conclusion: These observations support a functional role for Hnf4Î± in protecting the colonic mucosa against the initiation of the changes resembling inflammatory bowel diseases and polyp formation. Experiment Overall Design: HNF4alpha was conditionally knockout in the mouse epithelial colon with the villin CRE. A total of 3 control and 3 mutant littermates individuals were sacrificed at 1 year of age. The colon was harvested and Total RNA was isolated from each individuals. Each RNA sample was independently used to generate probes to screen affymetrix chips.

Project description:Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARM-NM-1 target genes. The aim of this study was to investigate the role of PPARM-NM-1 in heme-induced hyperproliferation and hyperplasia. Male PPARM-NM-1 KO and WT mice received a purified diet with or without heme. As PPARM-NM-1 is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARM-NM-1 leads to more surface injury and crypt hyperproliferation in the colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme-induced hyperproliferation in WT and KO mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in heme-fed KO mice. Our results suggest that the protective role of PPARM-NM-1 in antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by heme in PPARM-NM-1 KO mice. We conclude that PPARM-NM-1 plays a protective role in colon against oxidative stress, but PPARM-NM-1 does not mediate heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasia. Wild type and peroxisome proliferator-activated receptor alpha (PPARM-NM-1) knockout mice were fed a Westernized high fat diet, or the same diet supplemented with 0.5 M-BM-5mol heme/g diet. After 14 days of intervention, mice were killed and gene expression was profiled in colon.

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Role of HNF4alpha in the adult colon

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