title: Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.
  
  
  METHODS
  Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.
  
  
  RESULTS
  The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.
  
  
  CONCLUSIONS
  Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America; Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Thiago
authors.initials: T
authors.lastname: Almeida Pereira
authors.forename: Thiago Pereira
authors.initials: TP
authors.lastname: de Almeida
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Jerome
authors.initials: J
authors.lastname: Boursier
authors.affiliation: Division of Endocrinology, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Brittany
authors.initials: B
authors.lastname: Bohnic
authors.affiliation: Division of Pathology, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Guy
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000378:metabolism / Q000473:pathology; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000502:physiology; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D008715:Methionine; D002794:Choline