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 ␣ (TNF-␣) mRNA expression in wildtype, 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. (HEPATOLOGY 2001;34:101-108.)Bacterial lipopolysaccharide (LPS; endotoxin), an abundant and essential component of the outer membrane of gramnegative bacteria, provokes a generalized proinflammatory response in the infected host that sometimes leads to septic shock and multiple organ failure. 1,2 LPS also causes liver injury in many experimental models. 3,4 Chronic alcohol administration increases gut-derived endotoxin in the portal circulation, thereby activating Kupffer cells to produce several proinflammatory cytokines such as tumor necrosis factor ␣ (TNF-␣) and interleukin (IL)-1. 4,5 Indeed, intestinal sterilization with antibiotics (polymixin B and neomycin) 6 and reduction of gram-negative bacteria with lactobacillus feeding 7 prevented alcohol-induced liver injury, indicating that increased endotoxin levels in the portal circulation are involved in the development of early alcohol-induced liver injury.More than 30 years ago, mice of the C3H/HeJ strain were found to have a defective response to bacterial endotoxin. 8 Recent work showed that a mutation at the Lps locus is responsible for this effect and that C3H/HeJ mice have a missense mutation in the third exon of the toll-like receptor 4 (TLR4) gene encoded by Lps. 9 TLR4, a transmembrane protein with a cytoplasmic domain that bears homology to the IL-1 receptor, is expressed in monocytes and m...

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Background & Aims-The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with non-alcoholic steatohepatitis.

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