Hepatocyte-Specific HuR Protects Against Acetaminophen-Induced Liver Injury in Mice

Area of Science:

• Hepatology
• Molecular Biology
• Toxicology

Background:

• Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI).
• Hepatocyte proliferation, autophagy, and antioxidant capacity are vital for DILI prognosis.
• The precise molecular mechanisms underlying APAP-induced liver injury remain incompletely understood.

Purpose of the Study:

• To investigate the role of human antigen R (HuR) in APAP-induced liver injury.
• To elucidate the molecular mechanisms by which HuR influences liver injury, proliferation, autophagy, and antioxidant defense.

Main Methods:

• Utilized a mouse model of APAP-induced liver injury.
• Generated conditional hepatocyte-specific HuR knockout mice.
• Assessed liver injury, hepatocyte proliferation, autophagy markers (ATG3, ATG5, ATG7), and antioxidant capacity (NRF2) via protein expression analysis.
• Investigated HuR's interaction with target mRNA 3'-untranslated regions (UTRs) using molecular biology techniques.

Main Results:

• HuR protein expression was significantly upregulated in APAP-induced liver injury.
• Hepatocyte-specific knockout of HuR exacerbated APAP-induced liver injury.
• HuR deficiency led to reduced expression of cyclins (A1, B1, D1), CDK2, ATG proteins, and NRF2.
• These molecular changes correlated with decreased hepatocyte proliferation, autophagy, and antioxidant capacity.
• HuR was found to physically bind to the 3'-UTRs of target mRNAs, regulating their translation.

Conclusions:

• HuR plays a critical protective role in mitigating APAP-induced liver injury.
• HuR attenuates liver injury by promoting hepatocyte proliferation, autophagy, and antioxidant capacity.
• HuR's mechanism involves post-transcriptional regulation of key genes via mRNA 3'-UTR binding.