Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes
| Autor: | Maarten Hoogenkamp, Marianna Kruithof-de Julio, Vesna S. Stanulović, Irene Kyrmizi, Jacqueline L.M. Vermeulen, Theodorus B. M. Hakvoort, Iannis Talianidis, Wouter H. Lamers, Jan M. Ruijter |
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| Přispěvatelé: | Tytgat Institute for Liver and Intestinal Research, Medical Biology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Anatomie en Embryologie, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: NUTRIM - R2 - Gut-liver homeostasis |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
endocrine system Ornithine aminotransferase Molecular Sequence Data digestive system Mice chemistry.chemical_compound Glutamate-Ammonia Ligase Proliferating Cell Nuclear Antigen Internal medicine Glutamine synthetase Gene expression medicine Animals Mice Knockout Base Sequence Ornithine-Oxo-Acid Transaminase Hepatology biology Thyroid Hormone Receptors beta DNA Ornithine Molecular biology Upstream Enhancer Liver Regeneration Rats Proliferating cell nuclear antigen Glutamine Enhancer Elements Genetic Endocrinology Hepatocyte Nuclear Factor 4 Liver chemistry Hepatocytes biology.protein Phosphoenolpyruvate carboxykinase Phosphoenolpyruvate Carboxykinase (ATP) |
| Zdroj: | Hepatology (Baltimore, Md.), 45(2), 433-444. John Wiley and Sons Ltd Hepatology, 45(2), 433-444. Wiley |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.21456 |
| Popis: | In liver, most genes are expressed with a porto-central gradient. The transcription factor hepatic nuclear-factor4alpha (HNF4alpha) is associated with 12% of the genes in adult liver, but its involvement in zonation of gene expression has not been investigated. A putative HNF4alpha-response element in the upstream enhancer of glutamine synthetase (GS), an exclusively pericentral enzyme, was protected against DNase-I and interacted with a protein that is recognized by HNF4alpha-specific antiserum. Chromatin-immunoprecipitation assays of HNF4alpha-deficient (H4LivKO) and control (H4Flox) livers with HNF4alpha antiserum precipitated the GS upstream enhancer DNA only from H4Flox liver. Identical results were obtained with a histone-deacetylase1 (HDAC1) antibody, but antibodies against HDAC3, SMRT and SHP did not precipitate the GS upstream enhancer. In H4Flox liver, GS, ornithine aminotransferase (OAT) and thyroid hormone-receptor beta1 (TRbeta1) were exclusively expressed in pericentral hepatocytes. In H4LivKO liver, this pericentral expression remained unaffected, but the genes were additionally expressed in the periportal hepatocytes, albeit at a lower level. The expression of the periportal enzyme phosphoenolpyruvate carboxykinase had declined in HNF4alpha-deficient hepatocytes. GS-negative cells, which were present as single, large hepatocytes or as groups of small cells near portal veins, did express HNF4alpha. Clusters of very small GS- and HNF4alpha-negative, and PCNA- and OV6-positive cells near portal veins were contiguous with streaks of brightly HNF4alpha-positive, OV6-, PCNA-, and PEPCK-dim cells. Conclusion: Our findings show that HNF4alpha suppresses the expression of pericentral proteins in periportal hepatocytes, possibly via a HDAC1-mediated mechanism. Furthermore, we show that HNF4alpha deficiency induces foci of regenerating hepatocytes. (HEPATOLOGY 2007;45:433-444.). AD - AMC Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. |
| Databáze: | OpenAIRE |
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