Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.

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 l...

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Autores principales:	Yan Li, Muhammad Farooq, Donglai Sheng, Chanchal Chandramouli, Tian Lan, Nilesh K Mahajan, R Manjunatha Kini, Yunhan Hong, Thomas Lisowsky, Ruowen Ge
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e8718446ba8344fe9255bd58b4a8f4ae
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spelling	oai:doaj.org-article:e8718446ba8344fe9255bd58b4a8f4ae2021-11-18T07:29:14ZAugmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.1932-620310.1371/journal.pone.0030835https://doaj.org/article/e8718446ba8344fe9255bd58b4a8f4ae2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22292055/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Augmenter 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.Yan LiMuhammad FarooqDonglai ShengChanchal ChandramouliTian LanNilesh K MahajanR Manjunatha KiniYunhan HongThomas LisowskyRuowen GePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30835 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yan Li Muhammad Farooq Donglai Sheng Chanchal Chandramouli Tian Lan Nilesh K Mahajan R Manjunatha Kini Yunhan Hong Thomas Lisowsky Ruowen Ge Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
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.
format	article
author	Yan Li Muhammad Farooq Donglai Sheng Chanchal Chandramouli Tian Lan Nilesh K Mahajan R Manjunatha Kini Yunhan Hong Thomas Lisowsky Ruowen Ge
author_facet	Yan Li Muhammad Farooq Donglai Sheng Chanchal Chandramouli Tian Lan Nilesh K Mahajan R Manjunatha Kini Yunhan Hong Thomas Lisowsky Ruowen Ge
author_sort	Yan Li
title	Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
title_short	Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
title_full	Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
title_fullStr	Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
title_full_unstemmed	Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
title_sort	augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/e8718446ba8344fe9255bd58b4a8f4ae
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_version_	1718423445413298176

Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.

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