title: [Development and evaluation of a high-fat/high-fructose diet-induced nonalcoholic steatohepatitis mouse model].
abstract: OBJECTIVE
  To develop and evaluate a mouse model of nonalcoholic steatohepatitis (NASH) induced by a high-fat and high-fructose (HFHFr) diet.
  
  
  METHODS
  Six-week-old C3H mice were randomly divided into groups for HFHFr diet experimental modeling, high fat-only (HF) diet controls, high fructose-only (HFr) diet controls, and standard chow (SC) diet controls. The standard HFHFr diet was modified so that it consisted of 76.5% standard chow, 12% lard, 1% cholesterol, 5% egg yolk powder, 5% whole milk powder, and 0.5% sodium cholate, along with 20% fructose drinking water. At the end of experimental weeks 4, 8, and 16, measurements were taken for the NASH-related parameters of body mass, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lipid profile, and wet liver weight (upon sacrifice). In addition, histological changes in the liver were evaluated by hematoxylin-eosin (HE) and oil red O staining. The significance of differences between groups was assessed by statistical analysis, using the
  
  
  METHODS
  of t-test, Wilcoxon rank sum test, x2 test, F test or Fisher's test as appropriate.
  
  
  RESULTS
  As compared to the mice in the SC group at the corresponding time points, the mice in the HFHFr and HF groups showed significantly higher body mass and wet liver weight, as well as more extensive and robust lipid disposition in hepatic tissues as evidenced by oil red O staining. However, HE staining indicated that the HFHFr and HF groups had different degrees of macrosteatosis accompanied with intralobular inflammatory foci, with the former showing more remarkable NASH-related histological changes. Analysis at the end of week 16 showed that about 80% of the mice in the HFHFr group had developed NASH [nonalcoholic fatty liver disease (NAFLD) activity score (NAS): less than 5]. The levels of low-and high-density lipoprotein (LDL and HDL) cholesterol, as well as the levels of ALT and AST, were increased from the end of week 4 to the end of week 8 for the HFHFr and HF groups. At the end of week 16, the two groups differed in the extent of increase in total cholesterol and LDL and HDL cholesterol, with only the HFHFr group showing statistically significant changes. Specifically, at the end of week 16, the HFHFr group showed ALT levels of 108.5 +/- 93.34 U/L (F=5.099, P =0.005 vs. HF group: 44.30 +/- 35.71 U/L, HFr group: 46.70 +/- 17.95 U/L, SC group: 24.70 +/- 6.57 U/L), AST levels of 316.30 +/- 208.98 U/L (F=6.654, P=0.001 vs. HF: 132.12 +/- 75.43 U/L, HFr: 143.30 +/- 38.53 U/L, SC: 122.60 +/- 12.76 U/L), total cholesterol levels of 5.18 +/- 0.58 mmol/L (F=72: 470, P =0.000 vs. HF: 3.94 +/- 0.75 mmol/L, HFr: 2.30 +/- 0.50 mmol/L, SC: 2.02 +/- 0.24 mmol/L), HDL cholesterol levels of 3.05 +/- 0.49 mmol/L (F=25.413, P =0.000 vs. HF: 2.65 +/- 0.54 mmol/L HFr: 1.77 +/- 0.47 mmol/L, SC: 1.58 +/- 0.16 mmol/L), LDL cholesterol levels of 1.11 +/- 0.23 mmol/L (F =83.297, P =0.000 vs. HF: 0.72 +/- 0.17 mmol/L, HFr: 0.27 +/- 0.04 mmol/L, SC: 0.20 +/- 0.05 mmol/ L).
  
  
  CONCLUSIONS
  The present study suggests that a mouse model of NASH can be successfully induced by a 16-week modified HFHFr diet.
authors.affiliation: Zhejiang Chinese Medicine University, Hangzhou 310053, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yinlan
authors.initials: Y
authors.lastname: Liu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Qibin
authors.initials: Q
authors.lastname: Jiao
authors.forename: Jianyu
authors.initials: J
authors.lastname: Chen
authors.forename: Dongxue
authors.initials: D
authors.lastname: Bian
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ma
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Xun
authors.forename: Mingli
authors.initials: M
authors.lastname: Zhu
authors.forename: Junping
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005632:Fructose / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D005632:Fructose