title: Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death.
abstract: BACKGROUND
  Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response.
  
  
  OBJECTIVE
  The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells.
  
  
  METHODS
  Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells.
  
  
  RESULTS
  High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis.
  
  
  CONCLUSIONS
  High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.
authors: Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai ,P.R.China.
authors: Tongfang
authors: T
authors: Tang
authors: Yongheng
authors: Y
authors: Sui
authors: Min
authors: M
authors: Lian
authors: Zhiping
authors: Z
authors: Li
authors: Jing
authors: J
authors: Hua
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects*; D004357:Drug Synergism; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000276:immunology; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4