Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease
| Autor: | Bernard Fromenty, Claudia Mitchell, Alicia Mayeuf, Abdellah Mansouri, Marie-Anne Robin, Meriem Mahrouf-Yorgov, Hélène Gilgenkrantz |
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| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hépatotoxicité et xénobiotiques, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Necrosis
MESH : Blotting Western MESH : Hepatocytes MESH: Lipid Peroxidation MESH : Proto-Oncogene Proteins c-bcl-2 necrosis MESH: Hepatocytes Mice 0302 clinical medicine Fibrosis MESH: Reverse Transcriptase Polymerase Chain Reaction MESH : Bile Ducts MESH: Animals MESH: In Situ Nick-End Labeling MESH : Ligation Liver injury 0303 health sciences MESH: Electron Transport Complex I MESH : Lipid Peroxidation Reverse Transcriptase Polymerase Chain Reaction Histological Techniques MESH : Reverse Transcriptase Polymerase Chain Reaction apoptosis Fas receptor MESH : Mice Transgenic medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Caspases Hepatocyte MESH : In Situ Nick-End Labeling MESH : Histological Techniques [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology 030211 gastroenterology & hepatology medicine.symptom Programmed cell death medicine.medical_specialty MESH: Mice Transgenic Blotting Western Mice Transgenic Cholestasis Intrahepatic MESH: Histological Techniques Biology Pathology and Forensic Medicine 03 medical and health sciences Cholestasis Internal medicine MESH : Mice In Situ Nick-End Labeling medicine Animals MESH: Blotting Western Bcl-2 Ligation Molecular Biology MESH: Mice 030304 developmental biology MESH: Necrosis Electron Transport Complex I MESH: Caspases MESH: Cholestasis Intrahepatic MESH: Apoptosis MESH : Electron Transport Complex I fibrosis [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Cell Biology MESH: Ligation medicine.disease oxydative stress MESH : Necrosis Endocrinology MESH: Proto-Oncogene Proteins c-bcl-2 Apoptosis inflammation Hepatocytes MESH : Cholestasis Intrahepatic Bile Ducts Lipid Peroxidation MESH : Animals MESH : Caspases MESH: Bile Ducts cholestasis MESH : Apoptosis |
| Zdroj: | Laboratory Investigation Laboratory Investigation, 2011, 91 (2), pp.273-82. ⟨10.1038/labinvest.2010.163⟩ Laboratory Investigation, Nature Publishing Group, 2011, 91 (2), pp.273-82. 〈10.1038/labinvest.2010.163〉 Laboratory Investigation, Nature Publishing Group, 2011, 91 (2), pp.273-82. ⟨10.1038/labinvest.2010.163⟩ |
| ISSN: | 0023-6837 1530-0307 |
| DOI: | 10.1038/labinvest.2010.163⟩ |
| Popis: | International audience; The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression. |
| Databáze: | OpenAIRE |
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