Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation
| Autor: | Jessica M. Leonard, Natasha T. Snider, M. Bishr Omary, Anna S. Lok, Amika Singla, Shinichiro Hanada, Philip C. Andrews, Sujith V.W. Weerasinghe |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Pyridines
Mice Inbred Strains medicine.disease_cause Gene Expression Regulation Enzymologic Inclusion bodies Article Mice 03 medical and health sciences 0302 clinical medicine stomatognathic system medicine Animals Humans Glyceraldehyde 3-phosphate dehydrogenase Research Articles 030304 developmental biology Inclusion Bodies chemistry.chemical_classification Liver injury 0303 health sciences Reactive oxygen species Gene knockdown biology Liver Diseases Glyceraldehyde-3-Phosphate Dehydrogenases Cell Biology medicine.disease Molecular biology Nucleoside-diphosphate kinase 3. Good health Oxidative Stress medicine.anatomical_structure chemistry Nucleoside-Diphosphate Kinase 030220 oncology & carcinogenesis Hepatocyte Hepatocytes biology.protein Reactive Oxygen Species Oxidative stress |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Differential expression and activity of the cellular energy regulators GAPDH and NDPK underlie reactive oxygen species–induced damage in the mouse liver and may contribute to human liver disease progression. Genetic factors impact liver injury susceptibility and disease progression. Prominent histological features of some chronic human liver diseases are hepatocyte ballooning and Mallory-Denk bodies. In mice, these features are induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in a strain-dependent manner, with the C57BL and C3H strains showing high and low susceptibility, respectively. To identify modifiers of DDC-induced liver injury, we compared C57BL and C3H mice using proteomic, biochemical, and cell biological tools. DDC elevated reactive oxygen species (ROS) and oxidative stress enzymes preferentially in C57BL livers and isolated hepatocytes. C57BL livers and hepatocytes also manifested significant down-regulation, aggregation, and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH knockdown depleted bioenergetic and antioxidant enzymes and elevated hepatocyte ROS, whereas GAPDH overexpression decreased hepatocyte ROS. On the other hand, C3H livers had higher expression and activity of the energy-generating nucleoside-diphosphate kinase (NDPK), and knockdown of hepatocyte NDPK augmented DDC-induced ROS formation. Consistent with these findings, cirrhotic, but not normal, human livers contained GAPDH aggregates and NDPK complexes. We propose that GAPDH and NDPK are genetic modifiers of murine DDC-induced liver injury and potentially human liver disease. |
| Databáze: | OpenAIRE |
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