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Transcriptional Integration of Distinct Microbial and Nutritional Signals by the Small Intestinal Epithelium. Cell Mol Gastroenterol Hepatol 2022; 14:465-493. [PMID: 35533983 PMCID: PMC9305020 DOI: 10.1016/j.jcmgh.2022.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS The intestine constantly interprets and adapts to complex combinations of dietary and microbial stimuli. However, the transcriptional strategies by which the intestinal epithelium integrates these coincident sources of information remain unresolved. We recently found that microbiota colonization suppresses epithelial activity of hepatocyte nuclear factor 4 nuclear receptor transcription factors, but their integrative regulation was unknown. METHODS We compared adult mice reared germ-free or conventionalized with a microbiota either fed normally or after a single high-fat meal. Preparations of unsorted jejunal intestinal epithelial cells were queried using lipidomics and genome-wide assays for RNA sequencing and ChIP sequencing for the activating histone mark H3K27ac and hepatocyte nuclear factor 4 alpha. RESULTS Analysis of lipid classes, genes, and regulatory regions identified distinct nutritional and microbial responses but also simultaneous influence of both stimuli. H3K27ac sites preferentially increased by high-fat meal in the presence of microbes neighbor lipid anabolism and proliferation genes, were previously identified intestinal stem cell regulatory regions, and were not hepatocyte nuclear factor 4 alpha targets. In contrast, H3K27ac sites preferentially increased by high-fat meal in the absence of microbes neighbor targets of the energy homeostasis regulator peroxisome proliferator activated receptor alpha, neighbored fatty acid oxidation genes, were previously identified enterocyte regulatory regions, and were hepatocyte factor 4 alpha bound. CONCLUSIONS Hepatocyte factor 4 alpha supports a differentiated enterocyte and fatty acid oxidation program in germ-free mice, and that suppression of hepatocyte factor 4 alpha by the combination of microbes and high-fat meal may result in preferential activation of intestinal epithelial cell proliferation programs. This identifies potential transcriptional mechanisms for intestinal adaptation to multiple signals and how microbiota may modulate intestinal lipid absorption, epithelial cell renewal, and systemic energy balance.
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Lazebnik LB, Golovanova EV, Volel BA, Korochanskaya NV, Lyalyukova EA, Mokshina MV, Mekhtiev SN, Mekhtieva OA, Metsaeva ZV, Petelin DS, Simanenkov VI, Sitkin SI, Cheremushkin SV, Chernogorova MV, Khavkin АI. Functional gastrointestinal disorders. Overlap syndrome Clinical guidelines of the Russian Scientific Medical Society of Internal Medicine and Gastroenterological Scientific Society of Russia. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:5-117. [DOI: 10.31146/1682-8658-ecg-192-8-5-117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- L. B. Lazebnik
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - E. V. Golovanova
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - B. A. Volel
- I. M. Sechenov First Moscow Medical State University
| | - N. V. Korochanskaya
- Federal State Budgetary Educational Institution of Higher Education “Kuban State Medical University” Health Ministry of Russian Federation; State Budgetary Institution of Health Care “Region Clinic Hospital Nr 2” Health Ministry of Krasnodar Region
| | - E. A. Lyalyukova
- FSBEI VO “Omsk State Medical University” of the Ministry of Health
| | - M. V. Mokshina
- Institute of therapy a. instrumental diagnostics of FSBEI VO “Pacifi c State Medical Unuversity”
| | | | | | - Z. V. Metsaeva
- Republican clinical hospital of Health Care Ministry of Northen Ossetia- Alania Republic
| | - D. S. Petelin
- I. M. Sechenov First Moscow Medical State University
| | - V. I. Simanenkov
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. I. Sitkin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. V. Cheremushkin
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - M. V. Chernogorova
- Moscow regional research and clinical Institute of M. F. Vladimirsky; GBUZ MO “Podolsk City Clinical Hospital No. 3”
| | - А. I. Khavkin
- FSBAI HPE “N. I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation
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Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019; 25:4074-4091. [PMID: 31435165 PMCID: PMC6700705 DOI: 10.3748/wjg.v25.i30.4074] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Dustin E Bosch
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Sayed S Daoud
- Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States
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Klepsch V, Moschen AR, Tilg H, Baier G, Hermann-Kleiter N. Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD. Front Immunol 2019; 10:1070. [PMID: 31139192 PMCID: PMC6527601 DOI: 10.3389/fimmu.2019.01070] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/26/2019] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.
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Affiliation(s)
- Victoria Klepsch
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Gottfried Baier
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Chen BD, Chen XC, Pan S, Yang YN, He CH, Liu F, Ma X, Gai MT, Ma YT. TT genotype of rs2941484 in the human HNF4G gene is associated with hyperuricemia in Chinese Han men. Oncotarget 2018; 8:26918-26926. [PMID: 28460474 PMCID: PMC5432307 DOI: 10.18632/oncotarget.15851] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 02/20/2017] [Indexed: 12/26/2022] Open
Abstract
The aim of the study is to investigate the association between the human hepatocyte nuclear factor 4 gamma (HNF4G) gene and hyperuricemia in Chinese Han population. A total of 414 hyperuricemia patients and 406 gender and age-matched normouricemic controls were enrolled. Four single nucleotide polymorphisms were genotyped as genetic markers for the human HNF4G gene (rs2977939, rs1805098, rs2941484, rs4735692). Data were analyzed for two separate groups: men and women. For rs2941484, the genotype distribution frequency in hyperuricemic subjects and was significantly different from that in normouricemic controls in men (P = 0.038). Meanwhile, in recessive model of rs2941484, the distribution frequency of TT genotype and CC+CT genotypes also differed significantly between the hyperuricemia men and normouricemic men (P = 0.011). For the other 3 SNPs in both men and women, there was no difference in the genotype and allele and distribution frequency between the hyperuricemia patients and normouricemic controls. In men, after adjustments for BMI, SBP, DBP, fasting glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol and creatinine, the men with the TT genotype of rs2941484 were found to have significantly higher probability of suffering from hyperuricemia than the ones with CT and CC genotypes (OR = 2.170, P < 0.001). Therefore, TT genotype of rs2941484 in the human HNF4G gene might be a gender-specific genetic marker for hyperuricemia in Chinese Han men.
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Affiliation(s)
- Bang-Dang Chen
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiao-Cui Chen
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Shuo Pan
- First Department of Cardiology, People's Hospital of Shaanxi Province, Xi'an, China
| | - Yi-Ning Yang
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Chun-Hui He
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Fen Liu
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiang Ma
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Min-Tao Gai
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yi-Tong Ma
- Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Diamanti K, Umer HM, Kruczyk M, Dąbrowski MJ, Cavalli M, Wadelius C, Komorowski J. Maps of context-dependent putative regulatory regions and genomic signal interactions. Nucleic Acids Res 2016; 44:9110-9120. [PMID: 27625394 PMCID: PMC5100580 DOI: 10.1093/nar/gkw800] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 08/31/2016] [Indexed: 12/24/2022] Open
Abstract
Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected ∼144k putative regulatory regions among the human cell-lines, with the majority of them being ∼300 bp. We found ∼20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.
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Affiliation(s)
- Klev Diamanti
- Department of Cell and Molecular Biology, Uppsala University, Uppsala SE-751-24, Sweden
| | - Husen M Umer
- Department of Cell and Molecular Biology, Uppsala University, Uppsala SE-751-24, Sweden
| | - Marcin Kruczyk
- Department of Cell and Molecular Biology, Uppsala University, Uppsala SE-751-24, Sweden
| | - Michał J Dąbrowski
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala SE-751-08, Sweden
| | - Marco Cavalli
- Institute of Computer Science, Polish Academy of Sciences, Warsaw 012-48, Poland
| | - Claes Wadelius
- Institute of Computer Science, Polish Academy of Sciences, Warsaw 012-48, Poland
| | - Jan Komorowski
- Department of Cell and Molecular Biology, Uppsala University, Uppsala SE-751-24, Sweden .,Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala SE-751-08, Sweden
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7
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Baraille F, Ayari S, Carrière V, Osinski C, Garbin K, Blondeau B, Guillemain G, Serradas P, Rousset M, Lacasa M, Cardot P, Ribeiro A. Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF-4γ: A Critical Role for Enteroendocrine Cell Lineage. Diabetes 2015; 64:2744-56. [PMID: 25829452 DOI: 10.2337/db14-0993] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 03/21/2015] [Indexed: 11/13/2022]
Abstract
Intestine contributes to energy homeostasis through the absorption, metabolism, and transfer of nutrients to the organism. We demonstrated previously that hepatocyte nuclear receptor-4α (HNF-4α) controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4γ, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4γ knockout mice, we detect an exaggerated insulin peak and improvement in glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2, and Hnf4a, leading to an increase of both GLP-1-positive cell number and basal and stimulated GLP-1 plasma levels potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin (9-39), we demonstrate a direct effect of GLP-1 on improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic β-cells, and we report an increase of the β-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4γ improves glucose homeostasis through a modulation of the enteroendocrine cell lineage.
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Affiliation(s)
- Floriane Baraille
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Sami Ayari
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Véronique Carrière
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Céline Osinski
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Kevin Garbin
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Bertrand Blondeau
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Ghislaine Guillemain
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Patricia Serradas
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Monique Rousset
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
| | - Michel Lacasa
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Philippe Cardot
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France UMR_S 1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France
| | - Agnès Ribeiro
- Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
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VerHague MA, Cheng D, Weinberg RB, Shelness GS. Apolipoprotein A-IV Expression in Mouse Liver Enhances Triglyceride Secretion and Reduces Hepatic Lipid Content by Promoting Very Low Density Lipoprotein Particle Expansion. Arterioscler Thromb Vasc Biol 2013; 33:2501-8. [DOI: 10.1161/atvbaha.113.301948] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Melissa A. VerHague
- From the Department of Pathology (M.A.V., D.C., G.S.S.), Department of Internal Medicine (R.B.W.), and Department of Physiology & Pharmacology (R.B.W.), Wake Forest School of Medicine, Winston-Salem, NC
| | - Dongmei Cheng
- From the Department of Pathology (M.A.V., D.C., G.S.S.), Department of Internal Medicine (R.B.W.), and Department of Physiology & Pharmacology (R.B.W.), Wake Forest School of Medicine, Winston-Salem, NC
| | - Richard B. Weinberg
- From the Department of Pathology (M.A.V., D.C., G.S.S.), Department of Internal Medicine (R.B.W.), and Department of Physiology & Pharmacology (R.B.W.), Wake Forest School of Medicine, Winston-Salem, NC
| | - Gregory S. Shelness
- From the Department of Pathology (M.A.V., D.C., G.S.S.), Department of Internal Medicine (R.B.W.), and Department of Physiology & Pharmacology (R.B.W.), Wake Forest School of Medicine, Winston-Salem, NC
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9
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Saandi T, Baraille F, Derbal-Wolfrom L, Cattin AL, Benahmed F, Martin E, Cardot P, Duclos B, Ribeiro A, Freund JN, Duluc I. Regulation of the tumor suppressor homeogene Cdx2 by HNF4α in intestinal cancer. Oncogene 2012; 32:3782-8. [PMID: 22986531 DOI: 10.1038/onc.2012.401] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 07/16/2012] [Accepted: 07/17/2012] [Indexed: 12/21/2022]
Abstract
The gut-specific homeotic transcription factor Cdx2 is a crucial regulator of intestinal development and homeostasis, which is downregulated in colorectal cancers (CRC) and exhibits a tumor suppressor function in the colon. We have previously established that several endodermal transcription factors, including HNF4α and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4α in the mechanism of deregulation of Cdx2 in colon cancers. Crossing Apc(Δ14/+) mice prone to spontaneous intestinal tumor development with pCdx2-9LacZ transgenic mice containing the LacZ reporter under the control of the 9.3-kb Cdx2 promoter showed that this promoter segment contains sequences recapitulating the decrease of Cdx2 expression in intestinal cancers. Immunohistochemistry revealed that HNF4α, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apc(min/+) and Apc(Δ14/+)) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4α and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4α and Cdx2 in several experimental models of human colon cancer cell lines: xenografts in nude mice, wound healing and glucose starvation. Furthermore, Cdx2 decreased by knocking down HNF4α in human colon cancer cells using siRNA and in the colon of mice conditionally knocked out for the Hnf4α gene in the adult intestine (Hnf4α(f/f);VilCre(ERT2) mice). Finally, the conditionally knocked out mice Hnf4α(f/f);VilCre(ERT2) treated with the carcinogen AOM developed colorectal tumors earlier than wild-type mice, as previously reported for mice with a reduced Cdx2 expression. In conclusion, this study provides evidence that the downregulation of HNF4α is an important determinant of the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers. Consistently, similar to Cdx2, HNF4α exerts a tumor suppressor function in the colon in that its loss of function facilitates tumor progression.
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Affiliation(s)
- T Saandi
- Inserm, Unité 682, Strasbourg, France
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10
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Frochot V, Alqub M, Cattin AL, Carrière V, Houllier A, Baraille F, Barbot L, Saint-Just S, Ribeiro A, Lacasa M, Cardot P, Chambaz J, Rousset M, Lacorte JM. The transcription factor HNF-4α: a key factor of the intestinal uptake of fatty acids in mouse. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1253-63. [PMID: 22461026 DOI: 10.1152/ajpgi.00329.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
With an excessive postprandial accumulation of intestine-derived, triglyceride-rich lipoproteins being a risk factor of cardiovascular diseases, it is essential to characterize the mechanisms controlling the intestinal absorption of dietary lipids. Our aim was to investigate the role of the transcription factor hepatocyte nuclear factor (HNF)-4α in this process. We used transgenic mice with a specific and inducible intestinal knockout of Hnf-4α gene. One hour after a lipid bolus, in the presence of the lipase inhibitor tyloxapol, lower amounts of triglycerides were found in both plasma and intestinal epithelium of the intestine-specific Hnf-4α knockout (Hnf-4α(intΔ)) mice compared with the Hnf-4α(loxP/loxP) control mice. These discrepancies were due to a net decrease of the intestinal uptake of fatty acid in Hnf-4α(intΔ) mice compared with Hnf-4α(loxP/loxP) mice, as assessed by the amount of radioactivity that was recovered in intestine and plasma after gavage with labeled triolein or oleic acid, or in intestinal epithelial cells isolated from jejunum after a supply of labeled oleic acid-containing micelles. This decreased fatty acid uptake was associated with significant lower levels of the fatty acid transport protein-4 mRNA and protein along the intestinal tract and with a lower acyl-CoA synthetase activity in Hnf-4α(intΔ) mice compared with the control mice. We conclude that the transcription factor HNF-4α is a key factor of the intestinal absorption of dietary lipids, which controls this process as early as in the initial step of fatty acid uptake by enterocytes.
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Affiliation(s)
- Vincent Frochot
- Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMRS, Paris, France
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11
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Olsen AK, Boyd M, Danielsen ET, Troelsen JT. Current and emerging approaches to define intestinal epithelium-specific transcriptional networks. Am J Physiol Gastrointest Liver Physiol 2012; 302:G277-86. [PMID: 22094602 DOI: 10.1152/ajpgi.00362.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Upon developmental or environmental cues, the composition of transcription factors in a transcriptional regulatory network is deeply implicated in controlling the signature of the gene expression and thereby specifies the cell or tissue type. Novel methods including ChIP-chip and ChIP-Seq have been applied to analyze known transcription factors and their interacting regulatory DNA elements in the intestine. The intestine is an example of a dynamic tissue where stem cells in the crypt proliferate and undergo a differentiation process toward the villus. During this differentiation process, specific regulatory networks of transcription factors are activated to target specific genes, which determine the intestinal cell fate. The expanding genomewide mapping of transcription factor binding sites and construction of transcriptional regulatory networks provide new insight into how intestinal differentiation occurs. This review summarizes the current overview of the transcriptional regulatory networks driving epithelial differentiation in adult intestine. The novel technologies that have been implied to study these networks are presented and their prospects for implications in future research are also addressed.
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Affiliation(s)
- Anders Krüger Olsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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12
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Daigo K, Kawamura T, Ohta Y, Ohashi R, Katayose S, Tanaka T, Aburatani H, Naito M, Kodama T, Ihara S, Hamakubo T. Proteomic analysis of native hepatocyte nuclear factor-4α (HNF4α) isoforms, phosphorylation status, and interactive cofactors. J Biol Chem 2011; 286:674-86. [PMID: 21047794 PMCID: PMC3013027 DOI: 10.1074/jbc.m110.154732] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Hepatocyte nuclear factor-4α (HNF4α, NR2A1) is a nuclear receptor that has a critical role in hepatocyte differentiation and the maintenance of homeostasis in the adult liver. However, a detailed understanding of native HNF4α in the steady-state remains to be elucidated. Here we report the native HNF4α isoform, phosphorylation status, and complexes in the steady-state, as shown by shotgun proteomics in HepG2 hepatocarcinoma cells. Shotgun proteomic analysis revealed the complexity of native HNF4α, including multiple phosphorylation sites and inter-isoform heterodimerization. The associating complexes identified by label-free semiquantitative proteomic analysis include the following: the DNA-dependent protein kinase catalytic subunit, histone acetyltransferase complexes, mRNA splicing complex, other nuclear receptor coactivator complexes, the chromatin remodeling complex, and the nucleosome remodeling and histone deacetylation complex. Among the associating proteins, GRB10 interacting GYF protein 2 (GIGYF2, PERQ2) is a new candidate cofactor in metabolic regulation. Moreover, an unexpected heterodimerization of HNF4α and hepatocyte nuclear factor-4γ was found. A biochemical and genomewide analysis of transcriptional regulation showed that this heterodimerization activates gene transcription. The genes thus transcribed include the cell death-inducing DEF45-like effector b (CIDEB) gene, which is an important regulator of lipid metabolism in the liver. This suggests that the analysis of the distinctive stoichiometric balance of native HNF4α and its cofactor complexes described here are important for an accurate understanding of transcriptional regulation.
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Affiliation(s)
- Kenji Daigo
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Takeshi Kawamura
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Yoshihiro Ohta
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Riuko Ohashi
- the Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, and
| | - Satoshi Katayose
- the Tsukuba Research Laboratories, JSR Corporation, Ibaraki 305-0841, Japan
| | - Toshiya Tanaka
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Hiroyuki Aburatani
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Makoto Naito
- the Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, and
| | - Tatsuhiko Kodama
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Sigeo Ihara
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
| | - Takao Hamakubo
- From the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904
- To whom correspondence should be addressed: Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan. Tel./Fax: 81-3-5452-5231; E-mail:
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13
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Drozdowski LA, Clandinin T, Thomson ABR. Ontogeny, growth and development of the small intestine: Understanding pediatric gastroenterology. World J Gastroenterol 2010; 16:787-99. [PMID: 20143457 PMCID: PMC2825325 DOI: 10.3748/wjg.v16.i7.787] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Throughout our lifetime, the intestine changes. Some alterations in its form and function may be genetically determined, and some are the result of adaptation to diet, temperature, or stress. The critical period programming of the intestine can be modified, such as from subtle differences in the types and ratios of n3:m6 fatty acids in the diet of the pregnant mother, or in the diet of the weanlings. This early forced adaptation may persist in later life, such as the unwanted increased intestinal absorption of sugars, fatty acids and cholesterol. Thus, the ontogeny, early growth and development of the intestine is important for the adult gastroenterologist to appreciate, because of the potential for these early life events to affect the responsiveness of the intestine to physiological or pathological challenges in later life.
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14
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Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol Cell Biol 2009; 29:6294-308. [PMID: 19805521 DOI: 10.1128/mcb.00939-09] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatocyte nuclear factor 4alpha (HNF-4alpha) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4alpha loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4alpha led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/beta-catenin system. This control of the Wnt/beta-catenin signaling pathway by HNF-4alpha was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4alpha, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4alpha modulates Wnt/beta-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4alpha regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor.
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15
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Babeu JP, Darsigny M, Lussier CR, Boudreau F. Hepatocyte nuclear factor 4alpha contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation. Am J Physiol Gastrointest Liver Physiol 2009; 297:G124-34. [PMID: 19389805 DOI: 10.1152/ajpgi.90690.2008] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatocyte nuclear factor 4alpha (HNF4alpha) is a regulator of hepatocyte and pancreatic transcription. Hnf4alpha deletion in the mouse is embryonically lethal with severe defects in visceral endoderm formation. It has been concluded in the past that the role of Hnf4alpha in the developing colon was much less important than in the liver. However, the precise role of Hnf4alpha in the homeostasis of the small intestinal epithelium remains unclear. Our aim was to evaluate the potential of Hnf4alpha to support an intestinal epithelial phenotype. First, Hnf4alpha potential to dictate this phenotype was assessed in nonintestinal cell lines in vitro. Forced expression of Hnf4alpha in fibroblasts showed an induction of features normally restricted to epithelial cells. Combinatory expression of Hnf4alpha with specific transcriptional regulators of the intestine resulted in the induction of intestinal epithelial genes in this context. Second, the importance of Hnf4alpha in maintaining the homeostasis of the intestinal epithelium was investigated in mice. Mice conditionally deficient for intestinal Hnf4alpha developed normally throughout adulthood with an epithelium displaying normal morphological and functional structures with minor alterations. Subtle but statistical differences were observed at the proliferation and the cytodifferentiation levels. Hnf4alpha mutant mice displayed an increase in the number of goblet and enteroendocrine cells compared with controls. Given the fundamental role of this transcription factor in other tissues, these findings dispute the crucial role for this regulator in the maintenance of intestinal epithelial cell function at a period of time that follows cytodifferentiation but may suggest a functional role in instructing cells to become specific to the intestinal epithelium.
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Affiliation(s)
- Jean-Philippe Babeu
- Département d'Anatomie et de Biologie Cellulaire, Université de Sherbrooke,Canadian Institutes of Health Research Team on Digestive Epithelium, Sherbrooke, QC J1H 5N4, Canada
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16
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Alrefai WA, Wen X, Jiang W, Katz JP, Steinbrecher KA, Cohen MB, Williams IR, Dudeja PK, Wu GD. Molecular cloning and promoter analysis of downregulated in adenoma (DRA). Am J Physiol Gastrointest Liver Physiol 2007; 293:G923-34. [PMID: 17761837 DOI: 10.1152/ajpgi.00029.2007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Downregulated in adenoma (DRA), also referred to as SLC26A3, is an intestinal anion transporter essential for intestinal chloride absorption. Mutations in DRA result in congenital chloride diarrhea. DRA expression has been shown to be induced by differentiation and to be modulated by cytokines. However, mechanisms of DRA gene transcription and its tissue-specific targeting have not yet been investigated. In this study, we cloned a 3,765-bp promoter fragment of human DRA gene and characterized its activity in human colonic LS174T and Caco-2 human colon cell lines. Primer extension identified a single transcriptional initiation site that was identical in both colon cancer cell lines and normal colon. Although hepatic nuclear factor HNF-4 is involved in the basal activity of DRA promoter, sodium butyrate induces its activity in LS174T cells via the binding of Yin Yang 1 (YY1) and GATA transcription factors to their respective cis-elements in promoter region. We also demonstrated a reduction in DRA promoter activity in Caco-2 cells by IFN-gamma, suggesting that regulation of DRA promoter by IFN-gamma may contribute to the pathophysiology of intestinal inflammation. Furthermore, we showed that the DRA promoter fragment is sufficient to drive human growth hormone transgene expression specifically in villus epithelial cells of the small intestine and in differentiated upper crypt and surface epithelial cells of the colon. Our studies provide evidence for the involvement of HNF-4, YY1, and GATA transcription factors in DRA expression in intestinal differentiated epithelial cells.
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Affiliation(s)
- Waddah A Alrefai
- University of Illinois at Chicago, Jesse Brown VA Medical Center, Medical Research Service, Chicago, IL 60612, USA.
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17
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Leng S, Lu S, Yao Y, Kan Z, Morris GS, Stair BR, Cherny MA, Black DD. Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes. Am J Physiol Gastrointest Liver Physiol 2007; 293:G475-83. [PMID: 17556588 DOI: 10.1152/ajpgi.00072.2007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatocyte nuclear factor-4alpha (HNF-4alpha) regulates transcription of several genes involved in lipid metabolism, including that of apolipoprotein (apo) A-IV, which is tightly regulated by lipid absorption and enhances enterocyte chylomicron secretion. Studies were performed to define the role of HNF-4alpha in the regulation of apo A-IV gene transcription by dietary fatty acid in neonatal swine small intestine. HNF-4alpha mRNA was expressed in liver > intestine > kidney in suckling, weanling, and weaned pigs. Jejunal HNF-4alpha mRNA and protein and apo A-IV and swine microsomal triglyceride transfer protein (MTP) large subunit mRNA expression were induced in parallel in 2-day-old swine by a 24-h high-fat intraduodenal infusion. In IPEC-1 cells, incubation with oleic acid (OA) resulted in coordinate induction of both HNF-4alpha, apo A-IV, and MTP mRNA, similar to that observed in vivo. When HNF-4alpha expression was driven by doxycycline by using the TET-On system in the absence of OA to observe the effect of HNF-4alpha directly on apo A-IV and MTP mRNA levels in the absence of other factors that might be concomitantly induced by fatty acid absorption, apo A-IV and MTP expression were increased. In luciferase reporter gene assays in IPEC-1 cells using apo A-IV/C-III intergenic region constructs, TET-On-regulated HNF-4alpha expression without OA increased luciferase activity, and incubation with OA did not further increase activity. These data suggest that acute induction of the apo A-IV and MTP genes by dietary lipid in newborn intestine occurs, at least in part, via ligand-independent transactivation by HNF-4alpha that is itself induced by a lipid-mediated mechanism.
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Affiliation(s)
- Shuangying Leng
- Children's Foundation Research Center of Memphis, Le Bonheur Children's Medical Center, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
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18
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Klapper M, Böhme M, Nitz I, Döring F. The human intestinal fatty acid binding protein (hFABP2) gene is regulated by HNF-4alpha. Biochem Biophys Res Commun 2007; 356:147-52. [PMID: 17343826 DOI: 10.1016/j.bbrc.2007.02.091] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Accepted: 02/16/2007] [Indexed: 10/23/2022]
Abstract
The cytosolic human intestinal fatty acid binding protein (hFABP2) is proposed to be involved in intestinal absorption of long-chain fatty acids. The aim of this study was to investigate the regulation of hFABP2 by the endodermal hepatocyte nuclear factor 4alpha (HNF-4alpha), involved in regulation of genes of fatty acid metabolism and differentiation. Electromobility shift assays demonstrated that HNF-4alpha binds at position -324 to -336 within the hFABP2 promoter. Mutation of this HNF-4 binding site abolished the luciferase reporter activity of hFABP2 in postconfluent Caco-2 cells. In HeLa cells, this mutation reduced the activation of the hFABP2 promoter by HNF-4alpha by about 50%. Thus, binding element at position -336/-324 essentially determines the transcriptional activity of promoter and may be important in control of hFABP2 expression by dietary lipids and differentiation. Studying genotype interactions of hFABP2 and HNF-4alpha, that are both candidate genes for diabetes type 2, may be a powerful approach.
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Affiliation(s)
- Maja Klapper
- Molecular Nutrition, Institute of Human Nutrition and Food Science, Christian-Albrechts-University of Kiel, Heinrich-Hecht-Platz 10, D-24118 Kiel, Germany.
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19
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Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 2006; 58:798-836. [PMID: 17132856 DOI: 10.1124/pr.58.4.10] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Half of the members of the nuclear receptors superfamily are so-called "orphan" receptors because the identity of their ligand, if any, is unknown. Because of their important biological roles, the study of orphan receptors has attracted much attention recently and has resulted in rapid advances that have helped in the discovery of novel signaling pathways. In this review we present the main features of orphan receptors, discuss the structure of their ligand-binding domains and their biological functions. The paradoxical existence of a pharmacology of orphan receptors, a rapidly growing and innovative field, is highlighted.
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Affiliation(s)
- Gérard Benoit
- Unité Mixte de Recherche 5161 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique 1237, Institut Fédératif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, Lyon, France
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20
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Hanniman EA, Lambert G, Inoue Y, Gonzalez FJ, Sinal CJ. Apolipoprotein A-IV is regulated by nutritional and metabolic stress: involvement of glucocorticoids, HNF-4 alpha, and PGC-1 alpha. J Lipid Res 2006; 47:2503-14. [PMID: 16929032 DOI: 10.1194/jlr.m600303-jlr200] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Apolipoprotein A-IV (apoA-IV) is a 46 kDa glycoprotein that associates with triglyceride-rich and high density lipoproteins. Blood levels of apoA-IV generally correlate with triglyceride levels and are increased in diabetic patients. This study investigated the mechanisms regulating the in vivo expression of apoA-IV in the liver and intestine of mice in response to changes in nutritional status. Fasting markedly increased liver and ileal apoA-IV mRNA and plasma protein concentrations. This induction was associated with increased serum glucocorticoid levels and was abolished by adrenalectomy. Treatment with dexamethasone increased apoA-IV expression in adrenalectomized mice. Marked increases of apoA-IV expression were also observed in two murine models of diabetes. Reporter gene analysis of the murine and human apoA-IV/C-III promoters revealed a conserved cooperative activation by the hepatic nuclear factor-4 alpha (HNF-4 alpha) and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) but no evidence of a direct regulatory role for the glucocorticoid receptor. Consistent with these in vitro data, induction of apoA-IV in response to fasting was accompanied by increases in HNF-4 alpha and PGC-1 alpha expression and was abolished in liver-specific HNF-4 alpha-deficient mice. Together, these results indicate that the induction of apoA-IV expression in fasting and diabetes likely involves PGC-1 alpha-mediated coactivation of HNF-4 alpha in addition to glucocorticoid-dependent actions.
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Affiliation(s)
- Elyhisha A Hanniman
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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21
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Stegmann A, Hansen M, Wang Y, Larsen JB, Lund LR, Ritié L, Nicholson JK, Quistorff B, Simon-Assmann P, Troelsen JT, Olsen J. Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation. Physiol Genomics 2006; 27:141-55. [PMID: 16868071 DOI: 10.1152/physiolgenomics.00314.2005] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
DNA-binding transcription factors bind to promoters that carry their binding sites. Transcription factors therefore function as nodes in gene regulatory networks. In the present work we used a bioinformatic approach to search for transcription factors that might function as nodes in gene regulatory networks during the differentiation of the small intestinal epithelial cell. In addition we have searched for connections between transcription factors and the villus metabolome. Transcriptome data were generated from mouse small intestinal villus, crypt, and fetal intestinal epithelial cells. Metabolome data were generated from crypt and villus cells. Our results show that genes that are upregulated during fetal to adult and crypt to villus differentiation have an overrepresentation of potential hepatocyte nuclear factor (HNF)-4 binding sites in their promoters. Moreover, metabolome analyses by magic angle spinning (1)H nuclear magnetic resonance spectroscopy showed that the villus epithelial cells contain higher concentrations of lipid carbon chains than the crypt cells. These findings suggest a model where the HNF-4 transcription factor influences the villus metabolome by regulating genes that are involved in lipid metabolism. Our approach also identifies transcription factors of importance for crypt functions such as DNA replication (E2F) and stem cell maintenance (c-Myc).
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Affiliation(s)
- Anders Stegmann
- Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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22
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Garrison WD, Battle MA, Yang C, Kaestner KH, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 2006; 130:1207-20. [PMID: 16618389 PMCID: PMC3581272 DOI: 10.1053/j.gastro.2006.01.003] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2005] [Accepted: 12/14/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatocyte nuclear factor 4 alpha (HNF4alpha) is a transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4alpha might be required for development of the gut. METHODS Mouse embryos were generated in which Hnf4a was ablated in the epithelial cells of the fetal colon by using Cre-loxP technology. Embryos were examined by using a combination of histology, immunohistochemistry, DNA microarray, reverse-transcription polymerase chain reaction, electrophoretic mobility shift assays, and chromatin immunoprecipitation analyses to define the consequences of loss of HNF4alpha on colon development. RESULTS Embryos were recovered at E18.5 that lacked HNF4alpha in their colons. Although early stages of colonic development occurred, HNF4alpha-null colons failed to form normal crypts. In addition, goblet-cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4alpha contained HNF4alpha-binding sites within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4alpha in vivo. CONCLUSIONS HNF4alpha is a transcription factor that is essential for development of the mammalian colon, regulates goblet-cell maturation, and is required for expression of genes that control normal colon function and epithelial cell differentiation.
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Affiliation(s)
- Wendy D. Garrison
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michele A. Battle
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Chuhu Yang
- Department of Cell Biology and Neuroscience, University of California, Riverside, California
| | - Klaus H. Kaestner
- Department of Genetics, University of Pennsylvania Medical School, Philadelphia, Pennsylvania
| | - Frances M. Sladek
- Department of Cell Biology and Neuroscience, University of California, Riverside, California
| | - Stephen A. Duncan
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
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Peignon G, Thenet S, Schreider C, Fouquet S, Ribeiro A, Dussaulx E, Chambaz J, Cardot P, Pinçon-Raymond M, Le Beyec J. E-cadherin-dependent Transcriptional Control of Apolipoprotein A-IV Gene Expression in Intestinal Epithelial Cells. J Biol Chem 2006; 281:3560-8. [PMID: 16338932 DOI: 10.1074/jbc.m506360200] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cell-matrix and cell-cell adhesion play a central role in the control of cell proliferation, differentiation, and gene expression. Integrins and E-cadherin are the key components involved in these processes in epithelial cells. We recently showed that integrin-dependent adhesion to the extracellular matrix reinforces the formation of E-cadherin-actin complexes inducing the polarization of Caco-2 enterocytes and increases the expression of a marker of enterocyte differentiation, the apolipoprotein A-IV (apoA-IV) gene. By impairing or enhancing E-cadherin-dependent cell adhesion, we demonstrate in the present study its involvement in the transcriptional activation of the apoA-IV gene in Caco-2 cells. This control requires the regulatory sequence that we have previously identified as necessary and sufficient to drive and restrict apoA-IV gene expression in enterocytes in vivo. Furthermore, using chimeric E-cadherin-Fc homophilic ligand-coated surfaces, we show that a direct activation of E-cadherin triggers the transcriptional activation of the apoA-IV promoter. Finally, E-cadherin-dependent cell-cell adhesion controls the nuclear abundance of the transcription factor hepatic nuclear factor 4alpha, which is involved in the enterocyte-specific expression of apoA-IV gene. Altogether, our results suggest that E-cadherin controls enterocyte-specific expression of genes, such as the apoA-IV gene, through the control of hepatic nuclear factor 4alpha nuclear abundance.
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Affiliation(s)
- Gregory Peignon
- Université Pierre et Marie Curie UMRS 505, Paris, F-75006 France, INSERM, UMRS 505, F-75006 Paris, France
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