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Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice.

Abstract
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.
AuthorsTakehiko Uesugi, Matthias Froh, Gavin E Arteel, Blair U Bradford, Michael D Wheeler, Erwin Gäbele, Fuyumi Isayama, Ronald G Thurman
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 168 Issue 6 Pg. 2963-9 (Mar 15 2002) ISSN: 0022-1767 [Print] United States
PMID11884468 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Acute-Phase Proteins
  • Carrier Proteins
  • Cytokines
  • Endotoxins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Messenger
  • lipopolysaccharide-binding protein
  • Ethanol
  • Cytochrome P-450 CYP2E1
  • Alanine Transaminase
Topics
  • Acute-Phase Proteins
  • Alanine Transaminase (blood)
  • Animals
  • Carrier Proteins (genetics, physiology)
  • Cytochrome P-450 CYP2E1 (biosynthesis)
  • Cytokines (biosynthesis, genetics)
  • Endotoxins (blood)
  • Ethanol (toxicity, urine)
  • Female
  • Hepatitis, Alcoholic (immunology, metabolism, pathology, physiopathology)
  • Inflammation (immunology)
  • Intubation, Gastrointestinal (methods)
  • Lipopolysaccharides (metabolism)
  • Liver (enzymology, immunology, metabolism, pathology)
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size (drug effects)
  • RNA, Messenger (biosynthesis)
  • Weight Gain (drug effects)

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