Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin
| العنوان: | Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin |
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| المؤلفون: | Luca Quagliata, Patrizia Annunziata, Anna Barbato, Sergio Attanasio, Raffaele Castello, Pasquale Piccolo, Annamaria Carissimo, Luigi Terracciano, Nicola Brunetti-Pierri, Leandro Raul Soria |
| المصدر: | Hepatology. 66:124-135 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Genetically modified mouse, Aging, Carcinoma, Hepatocellular, Transgene, Down-Regulation, Mice, Transgenic, Biology, Statistics, Nonparametric, Mice, Random Allocation, 03 medical and health sciences, Liver disease, Downregulation and upregulation, alpha 1-Antitrypsin Deficiency, medicine, Animals, Humans, Transcription factor, Regulation of gene expression, Analysis of Variance, Hepatology, Liver Neoplasms, medicine.disease, Molecular biology, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Disease Models, Animal, Hepatocyte nuclear factors, 030104 developmental biology, medicine.anatomical_structure, Hepatocyte Nuclear Factor 4, Hepatocyte, Mutation |
| الوصف: | α1 -Antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due to protein misfolding with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing human ATZ have altered expression of a network of hepatocyte transcriptional factors, including hepatocyte nuclear factor-4α, that is early down-regulated and induces a transcriptional repression of ATZ expression. Reduced hepatocyte nuclear factor-4α was associated with activation of β-catenin, which regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Down-regulation of hepatocyte nuclear factor-4α expression and defective zonation in livers have not been recognized so far as features of the liver disease caused by ATZ and are likely involved in metabolic disturbances and in the increased risk of hepatocellular carcinoma in patients with AAT deficiency. Conclusion The findings of this study are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effects on metabolic liver functions. (Hepatology 2017;66:124-135). |
| تدمد: | 1527-3350 0270-9139 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b34d1c5fdaa7b384f7dd2bc1b2f34e2aTest https://doi.org/10.1002/hep.29160Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b34d1c5fdaa7b384f7dd2bc1b2f34e2a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15273350 02709139 |
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