Liver disease results from intrinsic causes, such as mitochondrial defects or cancer, or from exposure to external agents such as chemicals, toxins or viruses. Although a damaged liver can regenerate, acute liver damage and failure is normally treated by organ transplantation, which is hampered by a severe shortage of suitable donors and, even when successful, reduces patient life span significantly. To help improve transplant procedures, and ultimately to provide a source of healthy hepatic tissue, the process by which the liver regenerates, and how this process can be enhanced, needs to be better understood.

This paper describes a zebrafish model for liver regeneration. The authors used a forward genetic screen in which they chemically mutagenized zebrafish adult males and then looked for liver defects in their F3 progeny – this screen led to the identification of a mutant they called oliver. oliver mutants have an o-shaped liver (o-liver) of much reduced size owing to the depletion of most of the hepatocytes. oliver maps to the tomm22 gene, which encodes a translocase of the outer mitochondrial membrane, thought to play an important role in protein import into mitochondria. Morpholino injections, in which modified oligonucleotides (morpholinos) directed against tomm22 mRNA inhibited tomm22 translation, showed that knockdown of Tomm22 protein resulted in the same phenotype as that found in oliver mutants, thus confirming that tomm22 is required for hepatocyte survival. Importantly, as protein knockdown by morpholino only lasts until the morpholino is used up, the authors could show that when Tomm22 levels recovered, the liver mass also recovered, suggesting that liver damage caused by mitochondrial dysfunction can be reversible. Loss of the Wnt2b signaling pathway, which is required for liver development, inhibited the regeneration process in tomm22 morpholino-injected embryos, indicating some overlap in the control mechanisms between normal development and regeneration.

The ease of producing and screening large numbers of zebrafish makes the tomm22 liver regeneration assay suitable for large-scale chemical and genetic screens for molecules or genes modulating hepatocyte regeneration in the absence of most hepatocytes. tomm22 mutant fish will also be useful for identifying the lineage from which regenerating hepatocytes originate, and provide a whole-organism model for studying hepatic mitochondrial diseases.

2010