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(American Journal of Pathology. 2006;169:846-860.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050953

A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

Role of Peroxisome Proliferator-Activated Receptor-{alpha} and n-3 Polyunsaturated Fatty Acid Treatment on Liver Injury

Gianluca Svegliati-Baroni*, Cinzia Candelaresi*, Stefania Saccomanno*, Gianna Ferretti{dagger}, Tiziana Bachetti{dagger}, Marco Marzioni*, Samuele De Minicis*, Liliana Nobili{ddagger}, Renata Salzano§, Alessia Omenetti*, Deborah Pacetti, Soeren Sigmund||, Antonio Benedetti* and Alessandro Casini§**

From the Department of Gastroenterology,* Institute of Biochemistry,{dagger} and Department of Food Science, Polytechnic University of Marche, Ancona, Italy; the Clinical Pathology Laboratory,{ddagger} Preclinical Development, Nerviano Medical Sciences, Nerviano, Italy; the Nutrition Center and GI Unit,§ Department of Clinical Pathophysiology, University of Florence, Florence, Italy; the Department of Medicine,|| Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; and Multidisciplinary Center of Research on Food Sciences,** Florence, Italy

Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-{alpha} mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-{alpha} expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-{alpha}-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPAR{alpha} ligand, to HFD-treated animals restored hepatic adiponectin and PPAR{alpha} expression, reduced TNF-{alpha} hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPAR{alpha} down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury.




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