Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.
Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells and causes liver injury. Mice (C3H/HeJ) with mutations in toll-like receptor 4 (TLR4) are hyporesponsive to endotoxin. To test the hypothesis that TLR4 is involved in early alcohol-induced liver injury, the long-term intragastric ethanol feeding protocol developed by Tsukamoto and French for rats was adapted to mice. Animals with nonfunctional TLR4 and wild-type mice (C3H/HeOuJ) were compared. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 weeks. There was no difference in mean urine alcohol concentrations between the groups. Dietary alcohol significantly increased liver-to-body weight ratios and serum alanine transaminase (ALT) levels in wild-type mice (109 +/- 18 U/L) over high-fat controls (40 +/- 3 U/L), effects that were blunted significantly in mice with a mutation of TLR4 (55 +/- 9 U/L). While no significant pathologic changes were observed in high-fat controls, dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals (pathology score = 5.2 +/- 1.2). These pathologic changes were significantly lower in TLR4-deficient mice fed ethanol (score = 2.0 +/- 1.3). Endotoxin levels in the portal vein were increased significantly after 4 weeks in both groups fed ethanol. Moreover, ethanol increased tumor necrosis factor alpha (TNF-alpha) mRNA expression in wild-type, but not in TLR4-deficient, mice. These data are consistent with the hypothesis that Kupffer cell activation by endotoxin via TLR4 is involved in early alcohol-induced liver injury.
Uesugi
T
T
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA. uesugi@med.unc.edu
Froh
M
M
Arteel
G E
GE
Bradford
B U
BU
Thurman
R G
RG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage; D029721:Drosophila Proteins; D004731:Endotoxins / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage* / Q000652:urine; D005234:Fatty Liver / Q000139:chemically induced; D005260:Female; D006519:Hepatitis, Alcoholic / Q000209:etiology; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D009336:Necrosis; D009929:Organ Size; D011169:Portal Vein; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D004041:Dietary Fats; D029721:Drosophila Proteins; D004731:Endotoxins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000410:Alanine Transaminase