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Department of Pharmacology, Laboratory of Hepatobiology and Toxicology, University of North Carolina, Chapel Hill, NC 27599
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-
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- 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.
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