Keap1 deletion rescues cell death associated with Gpx4 loss in hepatocytes during acute liver injury

Date

Oct 18, 2024

Time

11:00 AM - 12:00 PM

Speaker

Leticia Colyn Pedrero

Affiliation

Department of Internal Medicine III, University Hospital RWTH Aachen, Germany

Language

en

Main Topic

Biologie

Host

Meritxell Huch

Description

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.

Last modified: Oct 18, 2024, 7:39:01 AM