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Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis

Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice...

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Autores principales: Weerasinghe, Sujith V. W., Park, Min-Jung, Portney, Daniel A., Omary, M. Bishr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063609/
https://www.ncbi.nlm.nih.gov/pubmed/27535425
http://dx.doi.org/10.1091/mbc.E15-06-0423
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author Weerasinghe, Sujith V. W.
Park, Min-Jung
Portney, Daniel A.
Omary, M. Bishr
author_facet Weerasinghe, Sujith V. W.
Park, Min-Jung
Portney, Daniel A.
Omary, M. Bishr
author_sort Weerasinghe, Sujith V. W.
collection PubMed
description Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice and cultured or treated with Fas ligand or acetaminophen after different culture times. Protein and mRNA expressions of Fas receptor, caspases-3/7/8, and Bak/Bax/Bid proteins were determined. FVB/N hepatocytes manifested rapid decreases of caspases-3/7 but not caspase-8 as culture time increased, which paralleled decreased susceptibility to apoptosis. Some changes were also found in Fas-receptor and Bak, Bax, and Bid proteins; caspase mRNA decreases were also noted. Caspase protein degradation was partially reversed by lysosomal protease but not proteasome or autophagy inhibitors. C57BL/6 and FVB/N hepatocytes behaved similarly in their limited susceptibility to apoptosis, whereas C3H/He hepatocytes show limited alterations in caspases, with consequent increased susceptibility to apoptosis. Similarly, C3H/He mice were more susceptible than C57BL/6 and FVB/N mice to Fas-mediated liver injury. Therefore there are significant mouse strain–dependent differences in susceptibility to apoptosis and selective loss of caspases upon short-term hepatocyte culture, with consequent decrease in susceptibility to apoptosis. These differences likely reflect genetic modifiers that provide resistance or predisposition to hepatocyte death.
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spelling pubmed-50636092016-12-30 Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis Weerasinghe, Sujith V. W. Park, Min-Jung Portney, Daniel A. Omary, M. Bishr Mol Biol Cell Brief Reports Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice and cultured or treated with Fas ligand or acetaminophen after different culture times. Protein and mRNA expressions of Fas receptor, caspases-3/7/8, and Bak/Bax/Bid proteins were determined. FVB/N hepatocytes manifested rapid decreases of caspases-3/7 but not caspase-8 as culture time increased, which paralleled decreased susceptibility to apoptosis. Some changes were also found in Fas-receptor and Bak, Bax, and Bid proteins; caspase mRNA decreases were also noted. Caspase protein degradation was partially reversed by lysosomal protease but not proteasome or autophagy inhibitors. C57BL/6 and FVB/N hepatocytes behaved similarly in their limited susceptibility to apoptosis, whereas C3H/He hepatocytes show limited alterations in caspases, with consequent increased susceptibility to apoptosis. Similarly, C3H/He mice were more susceptible than C57BL/6 and FVB/N mice to Fas-mediated liver injury. Therefore there are significant mouse strain–dependent differences in susceptibility to apoptosis and selective loss of caspases upon short-term hepatocyte culture, with consequent decrease in susceptibility to apoptosis. These differences likely reflect genetic modifiers that provide resistance or predisposition to hepatocyte death. The American Society for Cell Biology 2016-10-15 /pmc/articles/PMC5063609/ /pubmed/27535425 http://dx.doi.org/10.1091/mbc.E15-06-0423 Text en © 2016 Weerasinghe et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Brief Reports
Weerasinghe, Sujith V. W.
Park, Min-Jung
Portney, Daniel A.
Omary, M. Bishr
Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title_full Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title_fullStr Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title_full_unstemmed Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title_short Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis
title_sort mouse genetic background contributes to hepatocyte susceptibility to fas-mediated apoptosis
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063609/
https://www.ncbi.nlm.nih.gov/pubmed/27535425
http://dx.doi.org/10.1091/mbc.E15-06-0423
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