Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice.
Cellular responses to endotoxins are enhanced markedly by LPS-binding protein (LBP). Furthermore, it has been demonstrated that endotoxins and proinflammatory cytokines such as TNF-alpha participate in early alcohol-induced liver injury. Therefore, in this study, a long-term intragastric ethanol feeding model was used to test the hypothesis that LBP is involved in alcoholic hepatitis by comparing LBP knockout and wild-type mice. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. There was no difference in mean urine alcohol concentrations between the groups fed ethanol. Dietary alcohol significantly increased liver to body weight ratios and serum alanine aminotransferase levels in wild-type mice (189 +/- 31 U/L) over high-fat controls (24 +/- 7 U/L), effects which were blunted significantly in LBP knockout mice (60 +/- 17 U/L). Although no significant pathological changes were observed in high-fat controls, 4 wk of dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals as expected (pathology score, 5.9 +/- 0.5). These pathological changes were reduced significantly in LBP knockout mice fed ethanol (score, 2.6 +/- 0.5). Endotoxin levels in the portal vein were increased significantly after 4 wk in both groups fed ethanol. Moreover, ethanol increased TNF-alpha mRNA expression in wild-type, but not in LBP knockout mice. These data are consistent with the hypothesis that LBP plays an important role in early alcohol-induced liver injury by enhancing LPS-induced signal transduction, most likely in Kupffer cells.
Uesugi
Takehiko
T
Department of Pharmacology, Laboratory of Hepatobiology and Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
Froh
Matthias
M
Arteel
Gavin E
GE
Bradford
Blair U
BU
Wheeler
Michael D
MD
Gäbele
Erwin
E
Isayama
Fuyumi
F
Thurman
Ronald G
RG
D000209:Acute-Phase Proteins; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004731:Endotoxins / Q000097:blood; D000431:Ethanol / Q000633:toxicity* / Q000652:urine; D005260:Female; D006519:Hepatitis, Alcoholic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology; D007441:Intubation, Gastrointestinal / Q000379:methods; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D015430:Weight Gain / Q000187:drug effects; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000410:Alanine Transaminase; D002352:Carrier Proteins; D019392:Cytochrome P-450 CYP2E1; D016207:Cytokines; D004731:Endotoxins; D000431:Ethanol; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000099231:Lipopolysaccharide-Binding Protein