title: Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis.
abstract: Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor-deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating potential therapeutic strategies.
authors: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Michiko
authors: M
authors: Itoh
authors: Takayoshi
authors: T
authors: Suganami
authors: Nobutaka
authors: N
authors: Nakagawa
authors: Miyako
authors: M
authors: Tanaka
authors: Yukio
authors: Y
authors: Yamamoto
authors: Yasutomi
authors: Y
authors: Kamei
authors: Shuji
authors: S
authors: Terai
authors: Isao
authors: I
authors: Sakaida
authors: Yoshihiro
authors: Y
authors: Ogawa
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology*; D050356:Lipid Metabolism / Q000502:physiology; D008054:Lipid Peroxides / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology; D008113:Liver Neoplasms / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008054:Lipid Peroxides; D044105:Receptor, Melanocortin, Type 4; D014280:Triglycerides