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A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. In addition to hepatitis viral infections, several cohort studies have shown that diabetes mellitus is a risk factor of HCC, making the incidence alarming high. However, it has not been demonstrated directly how diabetes develops to HCC, because of its difficulty to follow changes of liver histology in diabetic populations. Here, we report that non-alcoholic steatohepatitis (NASH) is pivotal to link diabetes with HCC by establishing a novel, reproducible NASH–HCC model in mice. Neonatal male mice exposed to low-dose streptozotocin (STZ) developed liver steatosis with diabetes 1 week after feeding high-fat diet (HFD). Continuous HFD decreased hepatic fat deposit whilst increased lobular inflammation with foam cell-like macrophages, showing NASH pathology. In parallel with decreased phagocytosis of macrophages, fibroblasts accumulated to form “chicken-wired” fibrosis. All mice developed multiple HCC later. Female mice treated with STZ–HFD and male mice treated with STZ alone showed diabetes but never developed HCC by the absence of NASH-based fibrosis. Thus, the present study provides the evidence in novel mouse model that NASH-based fibrosis is an essential histological process for diabetic populations to accelerate the development of HCC.

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Acknowledgments

We are grateful to Professor Kenjiro Matsuno (Dokkyo Medical School) for reviewing the manuscript and thank Maki Sakurai for technical assistance.

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Authors and Affiliations

  1. Stelic Institute & Co, 1-9-15 Higashi Azabu, Minato-city, Tokyo, 106-0044, Japan

    Masato Fujii, Yuichiro Shibazaki, Kyoko Wakamatsu & Hiroyuki Yoneyama

  2. Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Yutaka Honda, Yusuke Kawauchi, Kenji Suzuki & Hitoshi Asakura

  3. Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan

    Somasundaram Arumugam & Kenichi Watanabe

  4. Department of Gastroenterology, Juntendo University School of Medicine, Shizuoka Hospital, Shizuoka, Japan

    Takafumi Ichida

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  1. Masato Fujii
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Correspondence to Hiroyuki Yoneyama.

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Fujii, M., Shibazaki, Y., Wakamatsu, K. et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol 46, 141–152 (2013). https://doi.org/10.1007/s00795-013-0016-1

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  • DOI: https://doi.org/10.1007/s00795-013-0016-1

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