Toll–Like Receptor 4 Is Involved in the Mechanism of Early Alcohol–Induced Liver Injury in Mice

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Abstract
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 α (TNF–α) 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.

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