ARRB1 downregulates acetaminophen-induced hepatoxicity through binding to p-eIF2α to inhibit ER stress signaling

Area of Science:

• Hepatology
• Molecular Biology
• Toxicology

Background:

• Acetaminophen (APAP) is a leading cause of drug-induced liver injury (DILI), with limited treatment options.
• β-Arrestin1 (ARRB1) plays a role in liver diseases, but its specific function in APAP-induced liver injury was unclear.

Purpose of the Study:

• To investigate the role of ARRB1 in APAP-induced liver injury.
• To determine if ARRB1 influences endoplasmic reticulum (ER) stress and apoptosis during APAP exposure.

Main Methods:

• Comparison of APAP-induced hepatotoxicity in wild-type and ARRB1 knockout mice.
• In vitro studies using hepatic cell lines (AML-12) and primary hepatocytes.
• Evaluation of histological changes, inflammation, ER stress markers (p-eIF2α, ATF4, CHOP), and apoptosis markers (cleaved caspase 3).
• Co-immunoprecipitation (Co-IP) assays to assess ARRB1 binding to ER stress components.

Main Results:

• ARRB1 knockout mice showed increased susceptibility to APAP-induced liver injury, characterized by greater necrosis, elevated liver enzymes (ALT, AST), and heightened inflammation.
• ARRB1 deficiency led to exacerbated ER stress and apoptosis in APAP-treated mice.
• Overexpression of ARRB1 mitigated APAP-induced ER stress and apoptosis.
• ARRB1 was found to directly bind to eIF2α and its phosphorylated form (p-eIF2α).

Conclusions:

• ARRB1 plays a protective role against APAP-induced liver injury.
• ARRB1 exerts its protective effects by targeting and reducing ER stress and apoptosis.
• ARRB1 represents a promising therapeutic target for managing APAP-induced DILI.