Hepatic ALR depletion: a potential therapeutic target for NASH-HCC?

Recent evidence has highlighted non-alcoholic steatohepatitis’ (NASH) predisposing role in the development of hepatocellular carcinoma (HCC). Despite this, the mechanisms underlying NASH-related HCC remain unknown. Identifying the molecular pathways contributing to the development of NASH-HCC is crucial to addressing this knowledge gap, and the determination of novel therapeutic targets for NASH-HCC remains a clinical priority.
PUBLISHED IN: Oncogene 2022

Comment:

Recent evidence has highlighted non-alcoholic steatohepatitis’ (NASH) predisposing role in the development of hepatocellular carcinoma (HCC). Despite this, the mechanisms underlying NASH-related HCC remain unknown. Identifying the molecular pathways contributing to the development of NASH-HCC is crucial to addressing this knowledge gap, and the determination of novel therapeutic targets for NASH-HCC remains a clinical priority.
Reduction in augmenter of liver regeneration (ALR), a key regulator of mitochondrial dynamics, is one such mechanism proposed to underlie NASH-driven HCC development.

The aim of this study was to evaluate the contribution of ALR ubiquitination-mediated degradation to NASH-driven HCC development. Firstly, the role of ALR in NASH-related HCC was established by assessing its expression in the livers of NASH-HCC patients via immunohistochemical staining. To test the relevance of ALR in NASH-HCC in vivo, both NASH and HCC were induced in mice with liver-specific deletion of ALR.

Key learnings:

ALR expression was found to be significantly decreased in patients with NASH-HCC. This downregulation was found to be negatively associated with HCC grade, a finding that was confirmed in vivo. Mice with liver-specific deletion of ALR were found to develop HCC earlier than their wild-type littermates.
In this mouse model, reductions in hepatic ALR were found to be the product of profound ubiquitination, i.e., imbalances between E3-ubiquitin (Ub) ligases and deubiquitinating enzymes (DUb) which were induced by murine double minute 2 (MDM2). This led to the activation of dynamin-related protein-1 (Drp1), which in turn caused disruptions in mitochondrial dynamics due to exacerbations in its fission. Ultimately, this resulted in the accelerated progression of NASH to HCC.
These findings suggest the importance of hepatic ALR depletion via dysregulation of ubiquitination in the development of NASH-HCC. Future studies should seek to verify this conclusion and investigate the potential role of ALR degradation as a therapeutic target for NASH-associated HCC.

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Dr. S Duarte

Dr. S Duarte

Articles: 56

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