Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis

Michiko Itoh, Takayoshi Suganami, Nobutaka Nakagawa, Miyako Tanaka, Yukio Yamamoto, Yasutomi Kamei, Shuji Terai, Isao Sakaida, Yoshihiro Ogawa

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122 Citations (Scopus)


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 receptordeficient 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.

Original languageEnglish
Pages (from-to)2454-2463
Number of pages10
JournalAmerican Journal of Pathology
Issue number5
Publication statusPublished - Nov 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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