title: Thioredoxin binding protein-2 mediates metabolic adaptation in response to lipopolysaccharide in vivo.
abstract: OBJECTIVE
  Endotoxin triggers a reorganization of the energy metabolic pathway, including the promotion of fatty acid utilization to adapt to a high energy demand during endotoxemia. However, the factors responsible for the metabolic adaptation and characteristic pathologies resulting from defective utilization fatty acids during endotoxin response have not been fully clarified. The thioredoxin binding protein-2 (TBP-2) knockout (TBP-2) mouse is an animal model of fatty acid oxidation disorder. The aim of this study was to determine whether and how TBP-2 is involved in metabolic regulation in a lipopolysaccharide (LPS)-induced endotoxemia model in mice.
  
  
  METHODS
  Prospective animal trial.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  TBP-2 and wild control mice.
  
  
  METHODS
  TBP-2 and wild control mice were intraperitoneally injected with LPS. Mortality, serum levels of markers of hepatorenal injuries, cytokines, insulin, glucose and lipid derivatives, and the hepatic signaling pathway regulating gluconeogenesis were investigated.
  
  
  RESULTS
  Following the administration of LPS, TBP-2 mice showed a predisposition for death without any significant elevation of inflammatory cytokines, compared to the wild mice. LPS-challenged TBP-2 mice showed fat deposition in the liver and kidney, organ injuries, glycogen depletion, and elevation of serum lipid derivatives such as free fatty acids, triglyceride and cholesterol. Hyperinsulinemia and hypoglycemia were observed in TBP-2 mice after LPS injection. Death due to the LPS administration was prevented by supplementation of glucose. Phosphorylation of Akt and FoxO1, an inhibitory pathway of gluconeogenesis in the liver of LPS-challenged TBP-2 mice was demonstrated, suggesting the enhancement of insulin signaling.
  
  
  CONCLUSIONS
  TBP-2 is involved in metabolic control during LPS-induced endotoxemia. After the LPS challenge, TBP-2 mice showed several characteristic aspects, such as hepatorenal injuries, and dysregulation of the lipid and glucose metabolisms. Furthermore, hypoglycemia promoted by hyperinsulinemia may be a critical risk factor for mortality in circumstances in which fatty acid utilization is impaired during endotoxemia.
authors.affiliation: Laboratory of Infection and Prevention, Department of Biological Response, Institute for Virus Research, Kyoto University, and Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kawahara-cho, Sakyo-ku Kyoto, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Oka
authors.forename: Wenrui
authors.initials: W
authors.lastname: Liu
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshihara
authors.forename: Md Kaimul
authors.initials: MK
authors.lastname: Ahsan
authors.forename: Dorys Adriana Lopez
authors.initials: DA
authors.lastname: Ramos
authors.forename: Aoi
authors.initials: A
authors.lastname: Son
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okuyama
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001774:Blood Chemical Analysis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D005227:Fatty Acids; D008070:Lipopolysaccharides; C445672:Txnip protein, mouse; D013879:Thioredoxins; D005947:Glucose