Keap1 deletion rescues cell death associated with Gpx4 loss in hepatocytes during acute liver injury
- Datum
- 18.10.2024
- Zeit
- 11:00 - 12:00
- Sprecher
- Leticia Colyn Pedrero
- Zugehörigkeit
- Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
- Sprache
- en
- Hauptthema
- Biologie
- Host
- Meritxell Huch
- Beschreibung
- Acute liver failure (ALF) is a life-threatening condition with limited treatment options beyond liver transplantation in non-acetaminophen cases. The extensive loss of liver function results from severe hepatocyte death, where elevated reactive oxygen species (ROS) play a significant role. Nuclear factor erythroid-2 like 2 (Nrf2) is crucial in ROS defense by regulating genes such as glutathione peroxidase 4 (GPX4), which prevents lipid peroxidation (LPO). GPX4 is involved in several regulated cell processes, including apoptosis and ferroptosis. GPX4 expression was measured in liver samples from healthy individuals, ALF, and acute-on-chronic liver failure (ACLF) patients. To investigate GPX4's role, mice with hepatocyte-specific deletion of Gpx4 (Gpx4Δhepa) and both Gpx4 and the Nrf2 repressor, Keap1, (Gpx4ΔhepaKeap1Δhepa) were generated. ALF was induced in mice using a carbon tetrachloride (CCl4) and a bile duct ligation (BDL) cholestasis model, each lasting 48 hours. ALF patients exhibited reduced GPX4 levels compared to healthy individuals and ACLF patients, consistent with observations in CCl4-treated wild- type mice. ALF-induced Gpx4Δhepa mice exhibited increased hepatocyte death and liver dysfunction upon CCl4 treatment, with increased apoptosis despite no changes in LPO markers. Activation of Nrf2 in Gpx4ΔhepaKeap1Δhepamice reversed CCl4-induced damage, reducing necrosis and apoptosis markers while inducing anti-apoptotic BCL2. Our results demonstrate that Gpx4 plays a critical role in ALF as its absence leads to hepatocyte apoptosis. Activating Keap1-dependent pathways targeting antioxidant defense system and upregulating BCL2 provides substantial protection against ALF in mice lacking Gpx4 in hepatocytes. Our findings suggest that the Keap1-Nrf2 axis is a promising therapeutic target in ALF.
Letztmalig verändert: 17.10.2024, 07:39:05
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Max Planck Institute of Molecular Cell Biology and GeneticsPfotenhauerstraße10801307Dresden
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- +49 351 210-2000
- MPI-CBG
- Homepage
- http://www.mpi-cbg.de
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