title: A diet-induced Sprague-Dawley rat model of nonalcoholic steatohepatitis-related cirrhosis.
abstract: Certain modified diets containing saturated fatty acids, cholesterol or fructose lead to the development of nonalcoholic steatohepatitis (NASH)-related fibrosis in rodents; however, progression to cirrhosis is rare. Experimental liver cirrhosis models have relied on genetic manipulation or administration of hepatotoxins. This study aimed to establish a reliable dietary model of NASH-related cirrhosis in a relatively short period. Male Sprague-Dawley rats (9 weeks of age) were randomly assigned to normal, high-fat (HF), or two types (1.25% or 2.5% cholesterol) of high-fat and high-cholesterol (HFC) diets for 18 weeks. All HFC diets contained 2% cholic acid by weight. Histopathological analysis revealed that the HFC diets induced obvious hepatic steatosis, inflammation with hepatocyte ballooning and advanced fibrosis (stage 3-4) in all 12 rats at 27 weeks of age. In contrast, all five rats given the HF diet developed mild steatosis and inflammation without fibrosis. The amount of cholesterol in the liver and hepatocellular mitochondrial and microsomal fractions was significantly higher in rats fed the HFC diets than the normal or HF diets. The HFC diets significantly suppressed mRNA levels of microsomal triglyceride transfer protein, adenosine triphosphate binding cassette transporter G5, bile acid CoA: amino acid N-acyltransferase and bile salt export pump, as well as the enzymatic activity of carnitine palmitoyltransferase in the liver. In conclusion, the HFC diets induced liver cirrhosis in conjunction with hepatic features of NASH in Sprague-Dawley rats within 18 weeks, and altered gene expression and enzyme activity to accumulate lipid and bile acid in the liver.
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan; Food Science and Nutrition, Human Life Science and Environmental Sciences, Nara Women's University, Nara, 630-8506, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ichimura
authors.affiliation: Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Masuzumi
authors.affiliation: Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Miku
authors.initials: M
authors.lastname: Kawase
authors.affiliation: Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Sakaki
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan; Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Tamaru
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan; Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan; Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Suruga
authors.affiliation: Department of Pathology and Laboratory Medicine, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Food Science and Nutrition, Human Life Science and Environmental Sciences, Nara Women's University, Nara, 630-8506, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan; Department of Nutrition, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, Nagasaki, 851-2195, Japan. Electronic address: omagari@sun.ac.jp.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Omagari
mesh_terms: D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D004195:Disease Models, Animal; D004798:Enzymes / Q000378:metabolism; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D009929:Organ Size; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
chemical_list: D002791:Cholesterol, Dietary; D004798:Enzymes; D014280:Triglycerides; D002784:Cholesterol
keywords: Animal model; Cholic acid; High-fat and high-cholesterol; Liver cirrhosis; Nonalcoholic steatohepatitis