title: Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies.
abstract: OBJECTIVE
  The methionine choline-deficient (MCD) diet leads to steatohepatitis in rodents. The aim of the present study was to investigate species, strain and sex differences in this nutritional model of non-alcoholic steatohepatitis (NASH).
  
  
  METHODS
  Male and female Wistar, Long-Evans and Sprague-Dawley rats, and C57/BL6 mice (n = 6 per group) were fed a MCD diet for 4 weeks. Control groups received an identical diet supplemented with choline bitartrate (0.2% w/w) and methionine (0.3% w/w). Liver pathology (steatosis and inflammation) and ultrastructure, liver lipid profile (total lipids, triglycerides, lipid peroxidation products), liver : body mass ratios and serum alanine aminotransferase (ALT) levels were compared between these groups.
  
  
  RESULTS
  The MCD diet-fed male rats developed greater steatosis (P < 0.001), had higher liver lipid content (P < 0.05) and had higher serum ALT levels (P < 0.005) than did female rats. Wistar rats (both sexes) had higher liver lipid levels (P < 0.05), serum ALT levels (P < 0.05), and liver mass : body mass ratios (P < 0.025) than did Long-Evans and Sprague-Dawley rats. In female groups, Wistar rats showed greater fatty change than did the other two strains (P < 0.05). All rats fed the MCD diet developed hepatic steatosis, but necrosis and inflammation were minor features and fibrosis was absent. Compared with Wistar rats, male C57/BL6 mice showed a marked increase in inflammatory foci (P < 0.001), end products of lipid peroxidation (free thiobarbituric acid reactive substances) (P < 0.005), and mitochondrial injury, while showing less steatosis (P < 0.005), lower hepatic triglyceride levels, (P < 0.005) and lower early lipid peroxidation products (conjugated dienes and lipid hydroperoxides; P < 0.005 and P < 0.01, respectively).
  
  
  CONCLUSIONS
  The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.
authors.affiliation: Department of Anatomical Pathology, University of Cape Town, Cape Town, Western Cape, 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: Enid G
authors.initials: EG
authors.lastname: Shephard
authors.forename: David A
authors.initials: DA
authors.lastname: Marais
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Jaffer
authors.forename: Vivienne E
authors.initials: VE
authors.lastname: Woodburne
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Kirsch
authors.forename: Pauline de la M
authors.initials: Pde L
authors.lastname: Hall
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D044342:Malnutrition / Q000150:complications*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012737:Sex Factors; D013045:Species Specificity
chemical_list: D008715:Methionine; D000410:Alanine Transaminase