Absence of JNK activity in hepatocytes exacerbates liver injury and fibrosis during chronic cholestasis in mice

Background:

The c-Jun NH2-terminal kinase (JNK) activation is required for cholestatic liver injury-induced fibrogenesis. Global JNK1 or JNK2 functions have been thoroughly addressed. Moreover, we showed that JNK1 function in hepatic stellate cells (HSCs), but not in hepatocytes mediates transactivation of HSCs during murine liver fibrosis. Here, we tested the hypothesis that JNK1 and JNK2 together in hepatocytes work to confer protection during cholestatic liver injury-induced liver fibrosis.

Methods:

The relevance of JNK in human and experimental cholestatic liver disease was tested. Additionally, Jnk1/2^f/f (WT) and Jnk1/2^Δhepa (hepatocyte-specific deletion of JNK1 and JNK2) mice were subjected to bile duct ligation (BDL) for 28 days. Mdr2 knockout mice were also used. Moreover, microarray analysis was performed.

Results:

Activation of JNK is characteristic in human (primary biliary cholangitis, PBC and primary sclerosing cholangitis, PSC) and in murine cholestasis (Mdr2^-/- and BDL). Serum markers of hepatic damage – liver transaminases – and liver histology revealed increased cell death, hepatic fibrogenesis, oxidative stress and inflammation in Jnk1/2^Δhepa mice compared to WT, 28-days after BDL. Furthermore, microarray analysis indicated protection of the mucosal epithelium since Mucin and Trefoil family members were strongly upregulated in absence of hepatocytic JNK1/2.

Conclusion:

Combined function of JNK1 and JNK2 in hepatocytes protects against the development of cholestatic liver disease.