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Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of  alr  in liver organogenesis in zebrafish model. We showed that  alr  is expressed in liver throughout hepatogenesis. Knockdown of  alr  through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of  alr  promotes liver growth. The small-liver phenotype in  alr  morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive Alr C131S  mutant promoted liver growth and rescued the liver growth defect of  alr  morphants. Nevertheless,  alr   C131S  is less efficacious in both functions. Meantime, high doses of  alr  MOs lead to widespread developmental defects and early embryonic death in an  alr  sequence-dependent manner. These results suggest that  alr  promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of  alr  in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of  alr  expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis.

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis