title: Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats.
abstract: OBJECTIVE
  Patients with non-alcoholic steatohepatitis (NASH) have increased mortality, including from infections. We, therefore, tested in a rodent model of steatohepatitis whether the hepatic acute phase response is intact.
  
  
  METHODS
  Steatohepatitis was induced in rats by feeding a high-fat, high-cholesterol diet for 4 (early) and 16 weeks (advanced NASH). 2 h after low-dose LPS (0.5 mg/kg i.p.), we measured the serum concentrations of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also measured liver mRNA's and the serum concentrations of acute phase proteins 24 h after LPS.
  
  
  RESULTS
  Non-alcoholic steatohepatitis in itself increased the liver mRNA levels of TNF-α and IL-6 and also the liver mRNA and serum levels of the acute phase proteins. The exposure to LPS increased serum TNF-α in both early and advanced NASH and more so than in the control rats. However, the increases in acute phase protein genes in liver tissue and proteins in the blood were lower than in the control rats.
  
  
  CONCLUSIONS
  In rats with early or advanced experimental NASH, LPS despite an increased interleukin release resulted in a blunted acute phase protein response. This tachyphylaxis may be part of the mechanism for the increased infection susceptibility of patients with NASH. We speculate that the steatosis-related interleukin release desensitises the signalling pathway leading to acute phase protein synthesis.
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, DK-8000, Denmark.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Thomsen
authors.forename: Lionel
authors.initials: L
authors.lastname: Hebbard
authors.forename: Emilie
authors.initials: E
authors.lastname: Glavind
authors.forename: Andrew
authors.initials: A
authors.lastname: Clouston
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004731:Endotoxins / Q000276:immunology*; D005260:Female; D007118:Immunoassay; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000209:Acute-Phase Proteins; D017931:DNA Primers; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
keywords: acute phase response; cytokines; inflammation; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; rats