JNKs protect from cholestatic liver disease progression by modulating Apelin signalling

Area of Science:

• Hepatology
• Molecular Biology
• Cell Biology

Background:

• Cholestatic liver injury involves c-Jun N-terminal kinases (JNK) activation.
• The specific role of JNK in hepatocytes during cholestasis remains unclear.

Purpose of the Study:

• To investigate the function of JNK1/2 in hepatocytes during cholestasis.
• To determine the hepatocyte-specific role of JNK during liver injury.

Main Methods:

• Analyzed patient samples with primary biliary cholangitis and primary sclerosing cholangitis.
• Generated hepatocyte-specific JNK1/2 knockout mice.
• Utilized bile duct ligation and carbon tetrachloride models for liver injury.
• Employed Apelin signaling inhibition and small interfering RNA (siRNA) for JNK1/2 targeting.

Main Results:

• JNK activation was elevated in human and animal cholestatic liver disease models.
• Hepatocyte-specific JNK1/2 deficiency exacerbated liver damage, fibrosis, and inflammation.
• JNK1/2 ablation in hepatocytes upregulated oxidative stress and Apelin signaling.
• Blocking Apelin signaling ameliorated liver injury and fibrosis in JNK1/2-deficient mice.
• In vivo siRNA targeting of JNK1/2 demonstrated a protective role.

Conclusions:

• JNK1 and JNK2 collaborate to protect hepatocytes from cholestatic liver disease via Apelin signaling.
• Targeting JNK signaling in hepatocytes is a viable therapeutic approach for cholestatic liver conditions.