title: Rodent nutritional model of steatohepatitis: effects of endotoxin (lipopolysaccharide) and tumor necrosis factor alpha deficiency.
abstract: OBJECTIVE
  Intestinal endotoxin (lipopolysaccharide) is thought to contribute to liver injury in both alcoholic and nonalcoholic steatohepatitis (NASH). Tumor necrosis factor alpha (TNFalpha) is an important mediator of this process and is considered central to the inflammatory response in NASH. This study aimed to investigate the effects of lipopolysaccharide on liver injury in the methionine choline deficient (MCD) nutritional model of NASH, and to determine if TNFalpha is required for the development of steatohepatitis in this model.
  
  
  METHODS
  Male C57/BL6 mice received a MCD diet for 4 weeks, whilst a control group received an identical diet supplemented with 0.2% choline bitartrate and 0.3% methionine. At 4 weeks, mice received either an intraperitoneal injection of lipopolysaccharide (0.5 microg/g body mass) or sterile saline, and were killed 24 h thereafter. In a separate study, TNFalpha knockout and wild type C57BL/6 mice received either MCD or control diets for 4 weeks. Serum transaminase levels, liver histology (steatosis, inflammation and apoptosis), hepatic triglyceride concentration and hepatic lipid peroxidation products (conjugated dienes, lipid hydroperoxides and thiobarbituric reactive substances, free and total) were evaluated.
  
  
  RESULTS
  Intraperitoneal administration of lipopolysaccharide augmented serum alanine aminotransferase (ALT) levels (P<0.02), hepatic inflammation (P<0.025), apoptosis (P<0.01) and free thiobarbituric acid reactive substances (P<0.025) in MCD mice. TNFalpha knockout mice fed the MCD diet developed steatohepatitis with histological and biochemical changes similar to those seen in wild type counterparts.
  
  
  CONCLUSIONS
  Lipopolysaccharide augments liver injury in MCD mice, and TNFalpha is not required for the development of steatohepatitis in MCD mice.
authors.affiliation: Department of Anatomical Pathology, Cape Heart Center and Medical Research Council, Cape Town, South Africa. rich@chempath.uct.ac.za
authors.forename: Richard
authors.initials: R
authors.lastname: Kirsch
authors.forename: Vivian
authors.initials: V
authors.lastname: Clarkson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Verdonk
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Marais
authors.forename: Enid G
authors.initials: EG
authors.lastname: Shephard
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Pauline
authors.initials: P
authors.lastname: de la M Hall
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D002796:Choline Deficiency / Q000097:blood / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced / Q000473:pathology*; D015227:Lipid Peroxidation; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D000410:Alanine Transaminase