Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

Cattin, Anne-Laure; Beyec, Johanne Le; Barreau, Frédérick; Saint-Just, Susan; Houllier, Anne; Gonzalez, Frank J.; Robine, Sylvie; Pinçon‐Raymond, Martine; Cardot, Philippe; Lacasa, Michel; Ribeiro, Agnès

doi:10.1128/mcb.00939-09

Cited by 146 publications

(150 citation statements)

References 55 publications

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“…Positive correlation between colonic HNF-4 ␣ / ␤ -catenin transcriptional activities and colonic proliferation and dedifferentiation apparently counters previous reports in which conditional intestinal HNF-4 ␣ knockout within a period following epithelial cellular determination was found to have only minor morphological and functional consequences compared with wild-type ( 16,42 ) or claimed to result in increased proliferation of crypt stem cells with increased activity of the ␤ -catenin/Tcf system ( 43 ). Although the disparity between the knockout studies concerned remains to be resolved, it is worth noting that the knockout data may imply an obligatory role of HNF-4 ␣ in modulating intestinal ontogenesis but may not predict the functional impact of fatty acyl ligands in modulating the transcriptional activity of prevalent HNF-4 ␣ .…”

Section: Discussioncontrasting

confidence: 51%

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

Algamas-Dimantov

Davidovsky

Ben-Ari

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org stationary, pluripotent stem cells at the base of the crypt give rise to rapidly proliferating cells that differentiate into postmitotic columnar absorptive colonocytes, mucinsecreting goblet cells, and enteroendocrine cells as they migrate from the crypt base to the surface, followed fi nally by their shedding into the intestinal lumen (reviewed in Ref. 1 ). Several signaling pathways, notably ␤ -catenin/Tcf and hepatocyte nuclear factor (HNF)-4 ␣ , modulate and control the proliferation and differentiation of adult colonocytes, whereas their perturbation via mutation or epigenetic modifi cation may ultimately result in colorectal cancer (CRC). Moreover, cell dedifferentiation correlates with key tumor features, such as tumor progression rates, invasiveness, drug resistance, and metastatic potential ( 2 ). Hence, perturbation of programming commitment during ontogenesis may mimic primary features of intestinal oncogenesis. In contrast to humans, major intestinal maturation processes of rodents take place only following birth ( 3 ), allowing for searching intestinal ontogenesis as a function of variable conditions reported to promote or suppress CRC.The metabolic syndrome (MetS) and its individual diseases (upper-body obesity, type 2 diabetes, dyslipidemia, and hypertension) are associated with an increased risk for CRC, and CRC incidence seems to be associated with the number of MetS components present at baseline (reviewed in Refs. 4, 5 ). Thus, the relative risk (RR) of CRC increases 2-fold with increase in waist circumference of MetS subjects ( 6 ), whereas the age-and sex-adjusted RR of CRC for an hemoglobin (Hb)A1c у 7% amounts to 2.94, compared with 1. Manuscript received 29 October 2011 and in revised form 20 February 2012. Published, JLR Papers in Press, February 22, 2012 DOI 10.1194 Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice Abbreviations: CRC, colorectal cancer; EPA, eicosapentaenoic acid; HE, hematoxylin and eosin; HNF-4 ␣ , hepatocyte nuclear factor 4 ␣ ; LA, linoleic acid; LBD, ligand binding domain; LCFA, long-chain fatty acid; MetS, metabolic syndrome; PCNA, proliferating cell nuclear antigen; RR, relative risk.

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Section: Discussioncontrasting

confidence: 51%

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

Algamas-Dimantov

Davidovsky

Ben-Ari

et al. 2012

Journal of Lipid Research

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“…HNF4α was found to be a subnetwork associated specifically with weaning (both induction and repression) in the small intestine and not with any other developmental transition in either the small intestine or colon (SI Appendix, Fig. S3), corroborating the role of HNF4 in small intestinal epithelial differentiation and biology (15). In contrast, HNF3α (FoxA1) was identified as a subnetwork specifically associated with weaning-repressed genes in both the small intestine and colon, and HNF3β (FoxA2) with developmental repression in the small intestine throughout weaning and adulthood transitions (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 55%

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

Rakoff-Nahoum

Kong

Kleinstein

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development.

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“…Therefore, we deduced that HNF4a might modulate the Wnt-b-catenin signaling pathway in both hepatic and HCC cells. A previous study indicated that HNF4a regulates the intestinal balance between proliferation and differentiation through regulating the Wnt-b-catenin signaling pathway (Cattin et al, 2009). However, the detailed and precise mechanisms are not known.…”

Section: Discussionmentioning

confidence: 99%

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Meng

Anjum

et al. 2013

Journal of Cell Science

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SummaryWnt-b-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4a is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4a maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-b-catenin signaling and HNF4a in the EMT process of HCC cells. Our results indicated that HNF4a expression was negatively regulated during Wnt-b-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4a was found to directly associate with TCF4 to compete with b-catenin but facilitate transcription corepressor activities, thus inhibiting expression of EMT-related Wnt-b-catenin targets. Moreover, HNF4a may control the switch between the transcriptional and adhesion functions of b-catenin. Overexpression of HNF4a was found to completely compromise the Wnt-b-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-b-catenin signaling and HNF4a in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-b-catenin signaling and HNF4a expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-b-catenin signaling or restoring HNF4a expression to prevent EMT.

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Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

Cited by 146 publications

References 55 publications

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

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

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

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