Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
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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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.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [64]
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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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