Cited by 206Liver Disease Diagnosis and TreatmentLiver physiology and pathologyImmune Response and Inflammation

Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice

Ye, Dewei, Li, Francois Y L, Lam, Karen S L, Li, Huating, Jia, Weiping, Wang, Yu, Man, Kwan, Lo, Chung Mau +2 more·2012·Gut

Abstract

BACKGROUND: Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. OBJECTIVE: Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. METHODS: ApoE(-/-)/TLR4(mut) mice and ApoE(-/-)/TLR4 wild-type mice (ApoE(-/-)/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE(-/-)) strain with TLR4-mutant (TLR4(mut)) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. RESULTS: ApoE(-/-)/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE(-/-)/TLR4(mut) mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE(-/-)/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE(-/-)/TLR4(mut) mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. CONCLUSIONS: These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.

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Crossref · 10.1136/gutjnl-2011-300269

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  • In ApoE-deficient mice given a high-fat and high-cholesterol diet, TLR4 deficiency reduces hepatic inflammation and injury.

    “In a model of NASH triggered by high-fat and high-cholesterol diet given to ApoE-deficient mice, TLR4 deficiency reduced hepatic inflammation and injury64.”

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Authors
Ye, D., Li, F. Y. L., Lam, K. S. L., Li, H., Jia, W., Wang, Y., Man, K., Lo, C. M., Li, X., & Xu, A.
Affiliations
  • University of Hong Kong (HK)
  • Shanghai Jiao Tong University (CN)
  • Wenzhou Medical University (CN)
Corresponding author
Xu, Aimin
Venue
Gut
Publisher
BMJ
Published
2012-01-17
Volume
61
Issue
7
Pages
1058-1067
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
OpenAlex
W2127144454
Cited by
206
References
41
Citations by year
2026: 3 · 2025: 5 · 2024: 16 · 2023: 7 · 2022: 10 · 2021: 22 · 2020: 18 · 2019: 12 · 2018: 16 · 2017: 19 · 2016: 19 · 2015: 28 · 2014: 15 · 2013: 12 · 2012: 4
FWCI
14.08
Type
journal article
Language
en
Open access
closed
Locations
  • Gut (publishedVersion)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
TLR4, nonalcoholic steatohepatitis, obesity, XBP1, unfolded protein response, Kupffer cells, reactive oxygen species, endotoxin, NF-κB, inflammatory cytokines, liver inflammation, steatosis, high-fat high-cholesterol diet, ApoE-deficient mice, liver fibrosis
MeSH terms
Regulatory Factor X Transcription Factors, X-Box Binding Protein 1, Animals, Dietary Fats, DNA-Binding Proteins, Fatty Liver, Kupffer Cells, Mice, Inbred C57BL, Obesity, Transcription Factors, NF-kappa B, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors, Toll-Like Receptor 4, Mice, Non-alcoholic Fatty Liver Disease

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