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Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research.

ABSTRACT: The adult liver of most vertebrates is predominantly comprised of hepatocytes. However, these cells must work in concert with biliary, stellate, vascular, and immune cells to accomplish the vast array of hepatic functions required for physiological homeostasis. Our understanding of liver development was accelerated as zebrafish emerged as an ideal vertebrate system to study embryogenesis. Through work in zebrafish and other models, it is now clear that the cells in the liver develop in a coordinated fashion during embryogenesis through a complex yet incompletely understood set of molecular guidelines. Zebrafish research has uncovered many key players that govern the acquisition of hepatic potential, cell fate, and plasticity. Although rare, some hepatobiliary diseases-especially biliary atresia-are caused by developmental defects; we discuss how research using zebrafish to study liver development has informed our understanding of and approaches to liver disease. The liver can be injured in response to an array of stressors including viral, mechanical/surgical, toxin-induced, immune-mediated, or inborn defects in metabolism. The liver has thus evolved the capacity to efficiently repair and regenerate. We discuss the emerging field of using zebrafish to study liver regeneration and highlight recent advances where zebrafish genetics and imaging approaches have provided novel insights into how cell plasticity contributes to liver regeneration.

SUBMITTER: Wang S

PROVIDER: S-EPMC6450094 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research.

Wang Shuang S Miller Sophie R SR Ober Elke A EA Sadler Kirsten C KC

Current topics in developmental biology 20170117

The adult liver of most vertebrates is predominantly comprised of hepatocytes. However, these cells must work in concert with biliary, stellate, vascular, and immune cells to accomplish the vast array of hepatic functions required for physiological homeostasis. Our understanding of liver development was accelerated as zebrafish emerged as an ideal vertebrate system to study embryogenesis. Through work in zebrafish and other models, it is now clear that the cells in the liver develop in a coordin ...[more]

PMID: 28335859

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Project description: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.

Dataset Information

Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research.

Publications

Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research.

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