Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g. high-fat diets) or overweight and insulin resistance (e.g. methionine-choline-deficient diets) or they are based on monogenetic defects (e.g. ob/ob mice). In the current study, a western-type diet containing soybean oil with high n 6-PUFA and 0.75% cholesterol (SOD+Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast a soybean oil-containing western-type diet without cholesterol (SOD) induced only mild steatosis but neither hepatic inflammation nor fibrosis, weight gain or insulin resistance. Another high-fat diet mainly consisting of lard and supplemented with fructose in drinking water (LAD+Fru) resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD+Cho but livers were devoid of inflammation and fibrosis. Although both LAD+Fru- and SOD+Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD+Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. Summarizing, dietary cholesterol in SOD+Cho diet may trigger hepatic inflammation and fibrosis. SOD+Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
University of Potsdam, Institute of Nutritional Science, Department for Nutritional Biochemistry; Nuthetal, Germany.
Janin
J
Henkel
University of Potsdam, Institute of Nutritional Science, Department for Nutritional Biochemistry; Nuthetal, Germany.
Charles Dominic
CD
Coleman
University of Potsdam, Institute of Nutritional Science, Department for Nutritional Biochemistry; Nuthetal, Germany.
Anne
A
Schraplau
Charité University Hospital Berlin, Institute of Pathology; Berlin, Germany.
Korinna
K
Jӧhrens
German Institute of Human Nutrition, Department of Molecular Toxicology; Nuthetal, Germany.|NutriAct - Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany.
Daniela
D
Weber
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|German Institute of Human Nutrition, Department of Molecular Toxicology; Nuthetal, Germany.|University of Porto, Faculty of Medicine, Department of Biomedicine; Porto, Portugal.|Institute for Innovation and Health Research (I3S), Aging and Stress Group; Porto, Portugal.
José Pedro
JP
Castro
German Institute of Human Nutrition, Department of Molecular Toxicology; Nuthetal, Germany.
Martin
M
Hugo
German Institute of Human Nutrition, Department of Adipocyte Development and Nutrition; Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
Tim Julius
TJ
Schulz
German Institute of Human Nutrition, Animal Facility; Nuthetal, Germany.
Stephanie
S
Krämer
German Institute of Human Nutrition, Department of Experimental Diabetology; Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
Annette
A
Schürmann
University of Potsdam, Institute of Nutritional Science, Department for Nutritional Biochemistry; Nuthetal, Germany.
Gerhard Paul
GP
Püschel
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D066273:Diet, Western; D022781:Hepatocytes / Q000187:drug effects; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D013024:Soybean Oil
D002791:Cholesterol, Dietary; D016207:Cytokines; D013024:Soybean Oil
Non-alcoholic fatty liver disease (NAFLD); cholesterol; hepatic inflammation; insulin resistance; metabolic syndrome; n-6 polyunsaturated fatty acids; obesity