RESUMO
In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS) mouse, which develops hereditary fatty liver and spontaneous liver tumors, we established a new congenic strain named FLS-Lep(ob). The Lep(ob) gene of the C57BL/6JWakShi (B6)-Lep(ob)/Lep(ob) mouse was transferred into the genome of the FLS mouse, by backcross mating. FLS-Lep(ob)/Lep(ob) mice were maintained by intercrossing between Lep(ob)-heterozygous littermates. The FLS-Lep(ob)/Lep(ob) mice of both sexes developed remarkable hyperphagia, obesity and type 2 diabetes mellitus. At 12 weeks of age, glucosuria was detected in all male and female FLS-Lep(ob)/Lep(ob) mice. Biochemical examination demonstrated that the FLS-Lep(ob)/Lep(ob) mice have severe hyperlipidemia and hyperinsulinemia. The livers of FLS-Lep(ob)/Lep(ob) mice showed microvesicular steatosis and deposition of large lipid droplets in hepatocytes throughout the lobules. The steatohepatitis-like lesions including the multifocal mononuclear cell infiltration and clusters of foamy cells were observed earlier in FLS-Lep(ob)/ Lep(ob) mice than in FLS mice. B6-Lep(ob)/Lep(ob) mice did not show hepatic inflammatory change. Furthermore, FLS-Lep(ob)/Lep(ob) mice developed multiple hepatic tumors including hepatocellular adenomas and carcinomas following steatohepatitis. In conclusion, the FLS-Lep(ob)/Lep(ob) mice developed steatohepatitis and hepatic tumors following hepatic steatosis. The FLS-Lep(ob)/Lep(ob) mouse with obesity and type 2 diabetes mellitus might be a useful animal model for human non-alcoholic steatohepatitis (NASH).
Assuntos
Adenoma de Células Hepáticas/genética , Carcinoma Hepatocelular/genética , Fígado Gorduroso/genética , Resistência à Insulina/genética , Neoplasias Hepáticas/genética , Adenoma de Células Hepáticas/sangue , Adenoma de Células Hepáticas/patologia , Animais , Carcinoma Hepatocelular/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Teste de Tolerância a Glucose , Glicosúria/sangue , Glicosúria/genética , Glicosúria/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Hiperlipidemias/sangue , Hiperlipidemias/genética , Hiperlipidemias/patologia , Leptina/genética , Leptina/metabolismo , Lipídeos/análise , Fígado/química , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/genética , Obesidade/patologia , RNA Mensageiro/metabolismoRESUMO
The fatty liver Shionogi (FLS) mouse is an inbred strain that develops spontaneous fatty liver (hepatic steatosis) chronically without obesity. Here, we reported that the mice develop spontaneous hepatocellular tumors with high incidences. The mice with age of over 1 year frequently developed whitish protuberant nodules in the livers, which were histologically diagnosed as hepatocellular adenoma and/or carcinoma (HCC). An incidence of HCC was 12/30 (40%) in males at 15-16 months of age, while in females that was 0/36 at 13-16 months and 4/42 (9.5%) at 20-24 months. Furthermore, histological examinations showed that after 2-4 months of age mononuclear cell infiltration and clusters of foamy cells appear in the fatty liver with elevated serum alanine aminotransferase, suggesting presence of inflammatory responses and liver injury. These observations show that the FLS mice develop hepatocellular tumors following steatohepatitis. The mouse might be a good animal model for investigating liver tumor and non-alcoholic steatohepatitis.