title: Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature Swine.
abstract: BACKGROUND
  Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model.
  
  
  METHODS
  Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24.
  
  
  RESULTS
  The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides.
  
  
  CONCLUSIONS
  This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.
authors.affiliation: Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Mouhamad
authors.initials: M
authors.lastname: Alloosh
authors.affiliation: Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.affiliation: Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Allison
authors.initials: A
authors.lastname: Fullenkamp
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Romil
authors.initials: R
authors.lastname: Saxena
authors.affiliation: School of Veterinary Medicine, Purdue University, Lafayette, Indiana, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Van Alstine
authors.affiliation: School of Biomedical Engineering, Purdue University, Lafayette, Indiana, United States of America.
authors.forename: Phelan
authors.initials: P
authors.lastname: Bybee
authors.affiliation: 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Klára
authors.initials: K
authors.lastname: Werling
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Sturek
authors.affiliation: Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.affiliation: Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Masuoka
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology; D002784:Cholesterol / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D005632:Fructose / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000209:etiology; D013552:Swine; D013556:Swine, Miniature
chemical_list: D004041:Dietary Fats; D005632:Fructose; D002784:Cholesterol