title: 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.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Dewei
authors.initials: D
authors.lastname: Ye
authors.forename: Francois Y L
authors.initials: FY
authors.lastname: Li
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Huating
authors.initials: H
authors.lastname: Li
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004041:Dietary Fats / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004041:Dietary Fats; D016328:NF-kappa B; D000071701:Regulatory Factor X Transcription Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat