title: Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome.
abstract: Metabolic syndrome is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases that affect the entire body. The hepatic manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). The basic pathogenesis of NAFLD/NASH remains controversial because it is difficult to clarify the disease process of NASH on the basis of metabolic syndrome alone. To determine the pathogenesis and effective treatment, an excellent animal model of NASH is required. Tsumura Suzuki obese diabetes (TSOD) male mice spontaneously develop diabetes mellitus, obesity, glucosuria, hyperglycemia, and hyperinsulinemia without any special treatments such as gene manipulation. In this study, we examined the histopathological characteristics of visceral fat and liver of 56 male TSOD mice aged 4-17 months and 9 male Tsumura Suzuki non-obesity (control) mice aged 6-12 months. In the visceral fat, enlargement of adipocytes and perivascular and pericapsular CD8-positive lymphoid aggregation were observed in 4-month-old mice. Abnormal expression of tumor necrosis factor-α, interleukin-6, and lipid peroxidation endo products was observed in macrophages. In the liver, microvesicular steatosis, hepatocellular ballooning, and Mallory bodies were observed in 4-month-old mice, with severity worsening with increasing time. These pathological findings in the liver mimic those seen in patients with NASH. Interestingly, small liver nodules with high cellularity and absence of portal tracts were frequently observed after 12 months. Most of them showed nuclear and structural atypia, and mimicked human hepatocellular carcinoma. The degree of steatosis in the non-tumor portions of the liver improved when the liver nodules developed. These findings were not observed in control mice. Here, we report that TSOD male mice spontaneously developed NAFLD without any special treatment, and that these mice are a valuable model for assessing NASH and NASH carcinogenesis owing to metabolic syndrome.
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishida
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nomoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Miwa
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Wataru
authors.initials: W
authors.lastname: Suzuki
authors.forename: Seiichi
authors.initials: S
authors.lastname: Iizuka
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Nagata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.forename: Masaki
authors.initials: M
authors.lastname: Aburada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Johji
authors.initials: J
authors.lastname: Imura
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000503:physiopathology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000473:pathology; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications*; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha