Papel del sistema Keap1/Nrf2 en hepatocitos durante el desarrollo de la enfermedad hepática
Oxidative stress is one of the pathophysiological mechanisms triggered in the development of acute and chronic liver disease (CLD). The Kelch-like ECH associated protein-1 (Keap1)/Erythroid 2-related factor 2 (Nrf2) system is of particular importance in redox homeostasis. Therefore, in the present s...
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/88658 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/88658 |
| Access Level: | acceso abierto |
| Palabra clave: | 616.36(043.2) Liver Hígado Medicina interna 3205 Medicina Interna |
| Sumario: | Oxidative stress is one of the pathophysiological mechanisms triggered in the development of acute and chronic liver disease (CLD). The Kelch-like ECH associated protein-1 (Keap1)/Erythroid 2-related factor 2 (Nrf2) system is of particular importance in redox homeostasis. Therefore, in the present study, we aimed to unveil the relevance of Keap1/Nrf2 system during the progression of acute and chronic liver disease. Methods. Liver biopsies were used from human patients underwent liver transplant due to a cetaminophen (APAP) overdose. In addition, liver biopsies from two different cohorts of non-alcoholic fatty liver disease (NAFLD) with and without liver fibrosiswere used. On one hand, 8–13-week-old male and female wild-type (WT) mice were treated with an intraperitoneal injection of APAP [0, 75, 150, 300 and 500 mg/kg] for 24 h. Furthermore, WT male and female mice were fed with Chow Diet (Control), Western Diet (WD), Ethanol 10% (EtOH) and DUAL diet for 23 weeks. Moreover, WT mice were challenged with repeated intraperitoneal injections of CCl4 [0,6ml/kg] for 28 days.In parallel, mice with hepatocyte-specific deletion of Keap1 (Keap1Δhepa) were challenged with a single intraperitoneal injection of APAP [500mg/kg] and sacrificed 6 h later. Additionally, the administration of DUAL diet was performed for23 weeks. Finally, mice were challenged with repeated doses of CCl4 [0,6ml/kg] at different time points (0-28 days). In all the experiments, Keap1fx/fx mice were used as control mice. After sacrificed, blood and tissue were collected for histopathological examination, protein evaluation and transcriptomic analysis. Lastly, Alexander cells were transfected with siKeap1 and treated with APAP[10mM] and Palmitic acid (P.A) [20μM] for 24 and 48 h respectively... |
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