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Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.
Hepatology. 2001 Jul; 34(1):101-8.Hep

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 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.

Authors+Show Affiliations

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA. uesugi@med.unc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11431739

Citation

Uesugi, T, et al. "Toll-like Receptor 4 Is Involved in the Mechanism of Early Alcohol-induced Liver Injury in Mice." Hepatology (Baltimore, Md.), vol. 34, no. 1, 2001, pp. 101-8.
Uesugi T, Froh M, Arteel GE, et al. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology. 2001;34(1):101-8.
Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U., & Thurman, R. G. (2001). Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology (Baltimore, Md.), 34(1), 101-8.
Uesugi T, et al. Toll-like Receptor 4 Is Involved in the Mechanism of Early Alcohol-induced Liver Injury in Mice. Hepatology. 2001;34(1):101-8. PubMed PMID: 11431739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. AU - Uesugi,T, AU - Froh,M, AU - Arteel,G E, AU - Bradford,B U, AU - Thurman,R G, PY - 2001/6/30/pubmed PY - 2001/7/28/medline PY - 2001/6/30/entrez SP - 101 EP - 8 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 34 IS - 1 N2 - 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. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/11431739/Toll_like_receptor_4_is_involved_in_the_mechanism_of_early_alcohol_induced_liver_injury_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270-9139(01)65119-X DB - PRIME DP - Unbound Medicine ER -