title: Saturated fat and cholesterol are critical to inducing murine metabolic syndrome with robust nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans.
  
  
  METHODS
  We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mice were sacrificed for histological analysis, markers of MetS, liver inflammation, circulating lipids, as well as liver staining for fibrosis and alpha smooth muscle actin (α-SMA).
  
  
  RESULTS
  We found that cholesterol significantly increased serum leptin, interleukin-6, liver weight and liver weight/body weight ratio, fibrosis and liver α-SMA.
  
  
  CONCLUSIONS
  Mice administered a diet accurately reflecting patterns associated with humans afflicted with MetS can reliably replicate features of MetS, NASH and significant liver fibrosis. The model we describe significantly reduces the time by several months for development of stage 3 hepatic fibrosis.
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Mells
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Ping P
authors.initials: PP
authors.lastname: Fu
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Tekla
authors.initials: T
authors.lastname: Smith
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Karpen
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. Electronic address: fanania@emory.edu.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D000199:Actins / Q000378:metabolism; D054392:Adipokines / Q000097:blood / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D066273:Diet, Western / Q000009:adverse effects*; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000209:etiology; D066248:High Fructose Corn Syrup / Q000009:adverse effects; D006865:Hydrogenation; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D009929:Organ Size; D013997:Time Factors
chemical_list: D000199:Actins; D054392:Adipokines; D015415:Biomarkers; D002791:Cholesterol, Dietary; D066248:High Fructose Corn Syrup; C544013:alpha-smooth muscle actin, mouse
keywords: Adipocytokine; Cholesterol; Fibrosis; Fructose; NASH