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Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
  1. Dewei Ye1,
  2. Francois Y L Li1,
  3. Karen S L Lam1,2,
  4. Huating Li3,
  5. Weiping Jia3,
  6. Yu Wang4,
  7. Kwan Man5,
  8. Chung Mau Lo5,
  9. Xiaokun Li6,
  10. Aimin Xu1,2,4
  1. 1Department of Medicine, The University of Hong Kong, Hong Kong
  2. 2Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong
  3. 3Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  4. 4Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong
  5. 5Department of Surgery, The University of Hong Kong, Hong Kong
  6. 6School of Pharmacy, Wenzhou Medical College, Wenzhou, China
  1. Correspondence to Dr Aimin Xu, Department of Medicine, The University of Hong Kong, Room L8-40, Lab Block, 21 Sassoon Road, Hong Kong; amxu{at}hku.hk

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−/−/TLR4mut mice and ApoE−/−/TLR4 wild-type mice (ApoE−/−/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE−/−) strain with TLR4-mutant (TLR4mut) 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−/−/TLR4mut 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−/−/TLR4mut 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.

  • Obesity
  • inflammation
  • fatty liver disease
  • oxidative stress
  • metabolic bone disease
  • liver
  • DNA damage
  • drug development
  • drug induced liver injury
  • drug resistance
  • drug toxicity
  • fatty liver
  • nonalcoholic steatohepatitis
  • cell biology

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Footnotes

  • DY and FYLL contributed equally to this work.

  • Funding This work is supported by Collaborative Research Fund (HKU5/CRF/08 and HKU4/CRF10) from the Research Grant Council of Hong Kong, Seeding fund for basic research from the University of Hong Kong (to AX), and the National Basic Research Program of China (2011CB504004).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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