title: A20 modulates lipid metabolism and energy production to promote liver regeneration.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Vascular Surgery, and the Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Scott M
authors: SM
authors: Damrauer
authors: Peter
authors: P
authors: Studer
authors: Cleide G
authors: CG
authors: da Silva
authors: Christopher R
authors: CR
authors: Longo
authors: Haley E
authors: HE
authors: Ramsey
authors: Eva
authors: E
authors: Csizmadia
authors: Gautam V
authors: GV
authors: Shrikhande
authors: Salvatore T
authors: ST
authors: Scali
authors: Towia A
authors: TA
authors: Libermann
authors: Manoj K
authors: MK
authors: Bhasin
authors: Christiane
authors: C
authors: Ferran
mesh_terms: D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3