A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

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A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

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dc.contributor.author Studer, Peter
dc.contributor.author Longo, Christopher R.
dc.contributor.author Csizmadia, Eva
dc.contributor.author Shrikhande, Gautam V.
dc.contributor.author Scali, Salvatore T.
dc.contributor.author Bhasin, Manoj K.
dc.contributor.author Selvarajoo, Kumar
dc.contributor.author Damrauer, Scott Michael
dc.contributor.author Da Silva, Cleide Gonsalves
dc.contributor.author Ramsey, Haley Elizabeth
dc.contributor.author Libermann, Towia Aron
dc.contributor.author Ferran, Christiane
dc.date.accessioned 2012-03-01T01:28:24Z
dc.date.issued 2011
dc.identifier.citation Damrauer, Scott M., Peter Studer, Cleide G. da Silva, Christopher R. Longo, Haley E. Ramsey, Eva Csizmadia, Gautam V. Shrikhande, Salvatore T. Scali, Towia A. Libermann, Manoj K. Bhasin, and Christiane Ferran. 2011. A20 modulates lipid metabolism and energy production to promote liver regeneration. PLoS ONE 6(3): e17715. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296049
dc.description.abstract Background: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-\(\kappa\)B 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.\(\beta\)galactosidase 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-\(\kappa\)B, 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0017715 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060102/pdf/ en_US
dash.license LAA
dc.title A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Damrauer, Scott Michael
dc.date.available 2012-03-01T01:28:24Z
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US

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