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A high‐fat diet and multiple administration of carbon tetrachloride induces liver injury and pathological features associated with non‐alcoholic steatohepatitis in mice
Author(s) -
Kubota Norihiro,
Kado Shoichi,
Kano Mitsuyoshi,
Masuoka Norie,
Nagata Yuriko,
Kobayashi Toshihide,
Miyazaki Kouji,
Ishikawa Fumiyasu
Publication year - 2013
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12102
Subject(s) - steatohepatitis , medicine , endocrinology , fatty liver , oxidative stress , fibrosis , liver injury , inflammation , carbon tetrachloride , glutathione , chemistry , biochemistry , enzyme , disease , organic chemistry
Summary The aim of the present study was to establish a progressive steatohepatitis mouse model because few reported animal models of non‐alcoholic steatohepatitis ( NASH ) show the progression from fatty liver to steatohepatitis. C 57 BL /6 N mice were fed a high‐fat diet ( HFD ) to develop obesity and were either administered carbon tetrachloride ( CC l 4 ) eight times (0.05 mL/kg, s.c., once, followed by 0.1 mL/kg, s.c., seven times) or not. Serum parameters and hepatic histopathology were examined. In a separate experiment, CC l 4 was administered subcutaneously from 0 to eight times to HFD ‐fed obese mice to investigate progressive changes. Markers of oxidative stress, inflammation and apoptosis, as well as histopathological changes in the liver, were analysed. The HFD ‐fed obese mice showed fatty liver but not steatohepatitis. In contrast, HFD ‐fed mice administered CC l 4 eight times showed histopathological features of steatohepatitis (fatty liver, inflammation, hepatocellular ballooning and fibrosis) and increased serum alanine aminotransferase levels. However, the multiple administration of CC l 4 to obese mice reduced the ratio of reduced glutathione to oxidized glutathione, superoxide dismutase activity and mitochondrial DNA copy number, leading to the development of chronic oxidative stress, increased numbers of apoptotic cells and increased levels of both tumour necrosis factor‐α and transforming growth factor‐β m RNA . The resulting inflammation led to increased hydroxyproline content in the liver and fibrosis. The present study demonstrates that multiple administration of CC l 4 to HFD ‐fed obese mice induces chronic oxidative stress that triggers inflammation and apoptosis and leads to the development of fibrosis in the liver, resulting in progression from fatty liver to steatohepatitis. This murine model will be useful in the research of hepatic disorders.