title: Systems Analysis of the Complement-Induced Priming Phase of Liver Regeneration.
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.
authors: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors: Jun S
authors: 0000-0001-6380-3351
authors: JS
authors: Min
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Robert A
authors: RA
authors: DeAngelis
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Edimara S
authors: 0000-0002-8438-275X
authors: ES
authors: Reis
authors: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors: Shakti
authors: S
authors: Gupta
authors: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors: Mano R
authors: 0000-0003-4249-067X
authors: MR
authors: Maurya
authors: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Charles
authors: 0000-0001-6698-5330
authors: C
authors: Evans
authors: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Arun
authors: 0000-0002-0883-1816
authors: A
authors: Das
authors: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Charles
authors: 0000-0001-9189-5003
authors: C
authors: Burant
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; shankar@ucsd.edu lambris@upenn.edu.
authors: John D
authors: JD
authors: Lambris
authors: 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.
authors: Shankar
authors: 0000-0002-8059-4659
authors: S
authors: Subramaniam
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D006498:Hepatectomy; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics* / Q000276:immunology*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009961:Orosomucoid / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D003176:Complement C3; D009961:Orosomucoid; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol