Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice.
Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP-adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct. In conclusion, LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/O270-9139/suppmat/index.html).
Su
Grace L
GL
Medical Service, Department of Veterans Affairs Medical Center and the Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. gsu@umich.edu
Gong
Ke Qin
KQ
Fan
Ming Hui
MH
Kelley
William M
WM
Hsieh
Jason
J
Sun
Jian Min
JM
Hemmila
Mark R
MR
Arbabi
Saman
S
Remick
Daniel G
DG
Wang
Stewart C
SC
D000082:Acetaminophen / Q000506:poisoning; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000256:Adenoviridae; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000097:blood; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011168:Portal System; D051381:Rats; D000099231:Lipopolysaccharide-Binding Protein
D000082:Acetaminophen; D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D003577:Cytochrome P-450 Enzyme System; D016207:Cytokines; D004731:Endotoxins; D005978:Glutathione; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein