Caspase 8 deletion reverses MASH progression following hepatocyte-specific JNK deletion

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder in the Western world. However, the mechanisms driving its progression to cirrhosis and hepatocellular carcinoma (HCC) remain unclear. c-Jun N-terminal kinases (JNKs) are known to play a significant role in liver health and disease. This study investigates the relevance of hepatocyte-specific JNK activation during experimental MASH initiation and progression.

Methods NASH was induced by a Western-style diet (WSD) in wild-type (WT) and hepatocyte-specific Jnk1 and Jnk2 deletion (JNK1/2Δhepa) mice. Caspase8/JNK1/2Δhepa mice were generated for further analysis.

Results JNK1/2Δhepa mice after WSD showed significantly increased transaminases, fibrosis, and inflammation compared to WT mice, evidenced by immune cell infiltration and elevated liver cytokines/chemokines. Gene pathway analysis revealed upregulation of apoptotic pathways, confirmed by TUNEL and Cleaved Caspase 3 staining. Adding caspase 8 deletion to JNK1/2Δhepa mice on WSD reduced transaminases, inflammation, fibrosis, and cell death. Intriguingly, pathway analysis demonstrated that most genes upregulated in JNK1/2Δhepa mice were reversed following additional caspase 8 knockdown. Deconvulation of RNA bulk data, based on unpublished liver single-cell datasets, revealed distinct increased immune cell populations in JNK1/2Δhepa mice, especially infiltrating macrophages and dendritic cells, which were reduced in Casp8/JNK1/2 Δhepa mice.

Conclusion Our findings suggest that Jnk1 and Jnk2 in hepatocytes play an essential role in modulating the oxidative stress response, which directs MASH initiation and progression via apoptotic cell death. Importantly, hepatocyte-specific caspase 8 is essential to modulate this response, suggesting caspase 8 as a promising therapeutic target for MASH.

 

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Publication History

Article published online:
23 January 2024