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A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration
BACKGROUND: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In thi...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060102/ https://www.ncbi.nlm.nih.gov/pubmed/21437236 http://dx.doi.org/10.1371/journal.pone.0017715 |
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author | Damrauer, Scott M. Studer, Peter da Silva, Cleide G. Longo, Christopher R. Ramsey, Haley E. Csizmadia, Eva Shrikhande, Gautam V. Scali, Salvatore T. Libermann, Towia A. Bhasin, Manoj K. Ferran, Christiane |
author_facet | Damrauer, Scott M. Studer, Peter da Silva, Cleide G. Longo, Christopher R. Ramsey, Haley E. Csizmadia, Eva Shrikhande, Gautam V. Scali, Salvatore T. Libermann, Towia A. Bhasin, Manoj K. Ferran, Christiane |
author_sort | Damrauer, Scott M. |
collection | PubMed |
description | BACKGROUND: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. METHODOLOGY AND PRINCIPAL FINDINGS: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. CONCLUSION: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients’ outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation. |
format | Text |
id | pubmed-3060102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30601022011-03-23 A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration Damrauer, Scott M. Studer, Peter da Silva, Cleide G. Longo, Christopher R. Ramsey, Haley E. Csizmadia, Eva Shrikhande, Gautam V. Scali, Salvatore T. Libermann, Towia A. Bhasin, Manoj K. Ferran, Christiane PLoS One Research Article BACKGROUND: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. METHODOLOGY AND PRINCIPAL FINDINGS: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. CONCLUSION: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients’ outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation. Public Library of Science 2011-03-17 /pmc/articles/PMC3060102/ /pubmed/21437236 http://dx.doi.org/10.1371/journal.pone.0017715 Text en Damrauer et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Damrauer, Scott M. Studer, Peter da Silva, Cleide G. Longo, Christopher R. Ramsey, Haley E. Csizmadia, Eva Shrikhande, Gautam V. Scali, Salvatore T. Libermann, Towia A. Bhasin, Manoj K. Ferran, Christiane A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title | A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title_full | A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title_fullStr | A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title_full_unstemmed | A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title_short | A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration |
title_sort | a20 modulates lipid metabolism and energy production to promote liver regeneration |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060102/ https://www.ncbi.nlm.nih.gov/pubmed/21437236 http://dx.doi.org/10.1371/journal.pone.0017715 |
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