title: In vivo consequence of vitamin C insufficiency in liver injury: vitamin C ameliorates T-cell-mediated acute liver injury in gulo(-/-) mice.
abstract: OBJECTIVE
  l-ascorbic acid (vitamin C) insufficiency is considered one of the major risk factors for the development of liver disease. However, its specific effects and related mechanisms in vivo are largely unknown. The objective of this study was to investigate the in vivo protective role of vitamin C and its related mechanisms in liver injury with Gulo(-/-) mice that cannot synthesize vitamin C like humans due to the lack of l-gulonolactone-γ-oxidase (Gulo), an essential enzyme for vitamin C synthesis.
  
  
  RESULTS
  When liver injury was induced in Gulo(-/-) mice by injection of concanavalin A (Con A), there was greater extensive liver damage accompanied by an increased number of apoptotic hepatocytes in vitamin C-insufficient Gulo(-/-) mice. Additionally, the plasma and hepatic levels of the proinflammatory cytokines, such as TNF-α and IFN-γ, were much higher in the vitamin C-insufficient Gulo(-/-) mice than in the control mice. Moreover, increased numbers of liver-infiltrating T-cells in the vitamin C-insufficient Gulo(-/-) mice were related to the increased hepatic levels of IFN-inducible factor (IP-10). Although the vitamin C-insufficient Gulo(-/-) mice had higher amounts of interleukin-22 (IL-22), a hepatoprotective cytokine, a defect in IL-22Rα expression and its downstream STAT3 activation in hepatocytes were found.
  
  
  METHODS
  We first demonstrate the novel in vivo action mechanisms of vitamin C on the prevention of disease development in the liver, through the regulation of excessive immune activation and maintenance of the IL-22Rα signaling pathways.
  
  
  CONCLUSIONS
  These results suggest that severe liver damage induced by inflammation could be prevented by sufficient supplementation with vitamin C.
authors.affiliation: 1 Department of Anatomy, Seoul National University College of Medicine , Seoul, Republic of Korea.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Bae
authors.forename: Chung-Hyun
authors.initials: CH
authors.lastname: Cho
authors.forename: Hyemin
authors.initials: H
authors.lastname: Kim
authors.forename: Yejin
authors.initials: Y
authors.lastname: Kim
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Hwang
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kang
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D001206:Ascorbic Acid Deficiency / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D050544:L-Gulonolactone Oxidase / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000975:Antioxidants; D016207:Cytokines; D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050544:L-Gulonolactone Oxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid