title: Lipopolysaccharide binding protein inhibitory peptide protects against acetaminophen-induced hepatotoxicity.
abstract: Acetaminophen (APAP)-induced liver injury remains the main cause of acute liver failure in the United States. Our previous work demonstrated that LPS binding protein (LBP) knockout mice are protected from APAP-induced hepatotoxicity. LBP is known to bind avidly to LPS, facilitating cellular activation. In this study, we sought to specifically inhibit the interaction between LBP and LPS to define the role of this interaction in APAP-induced liver injury. The peptide LBPK95A was able to inhibit LBP-mediated LPS activation of RAW 267.4 cells in a dose-dependent manner in vitro. In vivo, C57Bl/6 mice were treated with either LBPK95A or vehicle control concurrently with the administration of APAP (350 mg/kg). Mice treated with LBPK95A had significantly lower serum aspartate aminotransferase and alanine aminotransferase levels. Morphometric analysis of the liver tissue showed significantly less liver injury in mice treated with LBPK95A. To assess whether the LBPK95A altered glutathione depletion and APAP metabolism, we measured total glutathione levels in the liver after APAP. We found no difference in the glutathione levels and APAP-adduct formation between LBPK95A vs. vehicle control both at baseline and after APAP. In conclusion, our results support the hypothesis that LBP-induced liver injury after APAP is due to its ability to mediate activation by endogenous LPS. Our results suggest that blocking LBP-LPS interactions is a potential therapeutic avenue for the treatment of APAP-induced liver injury.
authors.affiliation: University of Michigan Medical School, Ann Arbor, 49109, USA. gsu@umich.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Su
authors.forename: L M
authors.initials: LM
authors.lastname: Hoesel
authors.forename: J
authors.initials: J
authors.lastname: Bayliss
authors.forename: M R
authors.initials: MR
authors.lastname: Hemmila
authors.forename: S C
authors.initials: SC
authors.lastname: Wang
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000595:Amino Acid Sequence; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000931:Antidotes; D016207:Cytokines; C555065:LPS binding protein (86-99), Ala(95)-; D008070:Lipopolysaccharides; D010455:Peptides; C082161:lipopolysaccharide A; D000082:Acetaminophen; D005978:Glutathione