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J Immunol. 2016 Sep 15;197(6):2500-8. doi: 10.4049/jimmunol.1600628. Epub 2016 Aug 10.

Systems Analysis of the Complement-Induced Priming Phase of Liver Regeneration.

Author information

1
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
3
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109;
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; shankar@ucsd.edu lambris@upenn.edu.
5
Graduate Program in Bioinformatics, Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093; Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093; and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 shankar@ucsd.edu lambris@upenn.edu.

Abstract

Liver regeneration is a well-orchestrated process in the liver that allows mature hepatocytes to reenter the cell cycle to proliferate and replace lost or damaged cells. This process is often impaired in fatty or diseased livers, leading to cirrhosis and other deleterious phenotypes. Prior research has established the role of the complement system and its effector proteins in the progression of liver regeneration; however, a detailed mechanistic understanding of the involvement of complement in regeneration is yet to be established. In this study, we have examined the role of the complement system during the priming phase of liver regeneration through a systems level analysis using a combination of transcriptomic and metabolomic measurements. More specifically, we have performed partial hepatectomy on mice with genetic deficiency in C3, the major component of the complement cascade, and collected their livers at various time points. Based on our analysis, we show that the C3 cascade activates c-fos and promotes the TNF-α signaling pathway, which then activates acute-phase genes such as serum amyloid proteins and orosomucoids. The complement activation also regulates the efflux and the metabolism of cholesterol, an important metabolite for cell cycle and proliferation. Based on our systems level analysis, we provide an integrated model for the complement-induced priming phase of liver regeneration.

PMID:
27511733
PMCID:
PMC5038987
DOI:
10.4049/jimmunol.1600628
[Indexed for MEDLINE]
Free PMC Article

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