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Cited by 488Alcohol Consumption and Health EffectsImmune Response and InflammationLiver physiology and pathology

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

Uesugi, Takehiko, Froh, Matthias, Arteel, Gavin E., Bradford, Blair U., Thurman, Ronald G.·2001·Hepatology
DOI 10.1053/jhep.2001.25350
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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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Crossref · 10.1053/jhep.2001.25350

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  • Global TLR4 deficiency in mice and gut sterilization with nonabsorbable antibiotics in rats reduce hepatic steatosis, oxidative stress and inflammation.

    “Global TLR4 deficiency in mice as well as gut sterilization with nonabsorbable antibiotics in rats reduces hepatic steatosis, oxidative stress and inflammation46–48.”

    From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [46]

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Authors
Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U., & Thurman, R. G.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Uesugi, Takehiko
ORCID
Arteel, Gavin E.
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2001-07
Volume
34
Issue
1
Pages
101-108
ISSN
0270-9139 (ISSN-L)
DOI
10.1053/jhep.2001.25350
OpenAlex
W2087051893
Cited by
488
References
36
Citations by year
2026: 7 · 2025: 6 · 2024: 14 · 2023: 10 · 2022: 19 · 2021: 15 · 2020: 18 · 2019: 18 · 2018: 32 · 2017: 28 · 2016: 31 · 2015: 27 · 2014: 26 · 2013: 19 · 2012: 30
FWCI
9.26
Type
journal article
Language
en
Open access
closed
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 5175 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
TLR4, alcohol-induced liver injury, endotoxin, Kupffer cells, TLR4-deficient mice, C3H/HeJ mice, TNF-α, steatosis, liver necrosis, chronic ethanol feeding, high-fat diet, alanine aminotransferase
MeSH terms
Alanine Transaminase, Ethanol, Animals, Body Weight, Dietary Fats, Endotoxins, Fatty Liver, Female, Hepatitis, Alcoholic, Liver, Liver Diseases, Alcoholic, Membrane Glycoproteins, Mice, Inbred C3H, Mutation, Necrosis, Organ Size, Portal Vein, Receptors, Cell Surface, RNA, Messenger, Tumor Necrosis Factor-alpha, Drosophila Proteins, Toll-Like Receptors, Toll-Like Receptor 4, Mice

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