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Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
Acetaminophen induces ER dependent signaling in mouse liver
Gábor Nagy1, Tamás Kardon, Lívius Wunderlich
1Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest POB 260, Hungary.
Archives of Biochemistry and Biophysics
|January 9, 2007
Summary
Acetaminophen overdose causes liver injury by disrupting the endoplasmic reticulum (ER) redox balance. This ER stress triggers proapoptotic signaling, leading to hepatocyte apoptosis.
Area of Science:
- Hepatology
- Cell Biology
- Toxicology
Background:
- Acetaminophen (AAP) overdose is a leading cause of acute liver failure.
- The role of the endoplasmic reticulum (ER) in AAP-induced liver injury remains incompletely understood.
Purpose of the Study:
- To investigate the involvement of the ER in acetaminophen-induced hepatocellular damage.
- To elucidate the specific ER stress pathways activated by AAP.
Main Methods:
- In vivo mouse model of AAP-induced liver injury.
- Analysis of glutathione levels, ER redox state, and ER stress markers (ATF6, GADD153/CHOP).
- Assessment of ER-resident caspase activation and hepatocyte apoptosis.
Main Results:
- AAP treatment decreased glutathione levels and shifted ER redox state towards oxidation.
- Activation of ER stress transcription factors ATF6 and GADD153/CHOP was observed.
- Transient caspase-12 activation and increased hepatocyte apoptosis occurred, without caspase-3 or -8 activation.
Conclusions:
- Intraluminal ER redox imbalance is a key event in AAP-induced liver injury.
- Consequential ER stress signaling and proapoptotic events contribute to hepatocellular damage.
- Glutathione depletion alone is insufficient to induce AAP-like apoptosis.
