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Tsumura-Suzuki obese diabetic mice-derived hepatic tumors closely resemble human hepatocellular carcinomas in metabolism-related genes expression and bile acid accumulation

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Abstract

Background and aims

Tsumura-Suzuki obese diabetic (TSOD) is a good model of metabolic syndrome showing typical lesions found in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and develops spontaneous hepatic tumors with a high frequency. Majority of the developing tumors overexpress glutamine synthetase (GS), which is used as a marker of hepatocellular carcinoma (HCC). The aim of this study is to assess the status of expression of metabolism-related genes and the level of bile acids in the TSOD mice-derived tumors and to determine the association with metabolic dysregulation between human HCC and TSOD mice-derived tumors.

Methods

GS-positive hepatic tumors or adjacent normal tissues from 71-week-old male TSOD mice were subjected to immunohistochemical staining, quantitative RT-PCR (qRT-PCR), quantitation of cholic acid and taurocholic acid.

Results

We found that downregulation of the rate-limiting enzyme for betaine synthesis (BADH), at both mRNA and protein levels in GS-positive TSOD mice-derived tumors. Furthermore, the bile acid receptor FXR and the bile acid excretion pump BSEP (Abcb11) were found to be downregulated, whereas BAAT and Akr1c14, involved in primary bile acid synthesis and bile acid conjugation, were found to be upregulated at mRNA level in GS-positive TSOD mice-derived tumors. BAAT and Akr1c14 were also overexpressed at protein levels. Total cholic acid was found to be increased in GS-positive TSOD mice-derived tumors.

Conclusion

Our results strongly support the significance of TSOD mice as a model of spontaneously developing HCC.

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Abbreviations

TSOD:

Tsumura-Suzuki obese diabetic

GS:

Glutamine synthetase

HCC:

Hepatocellular carcinoma

IHC:

Immunohistochemical staining

qRT-PCR:

Quantitative RT-PCR

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Acknowledgements

We thank Megimi Kume, Hitomi Umemoto, Yuki Morimoto, and Chitose Maruyama for their help and technical assistance during the histological experiments and LC/ESI–MS.

Funding

This study was supported by JSPS KAKENHI Grant Numbers JP15K15098 to K. Tsuneyama and JP15K06783 to T. Takahashi.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, 202-8585, Japan

    Tetsuyuki Takahashi & Takao Hijikata

  2. Phenex Pharmaceuticals AG, 69123, Heidelberg, Germany

    Ulrich Deuschle

  3. Department of Bioscience, Fukui Prefectural University, Fukui, 910-1195, Japan

    Shu Taira

  4. Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan

    Takeshi Nishida

  5. Department of Japanese Oriental Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan

    Makoto Fujimoto

  6. Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan

    Koichi Tsuneyama

Authors
  1. Tetsuyuki Takahashi
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  2. Ulrich Deuschle
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  3. Shu Taira
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  4. Takeshi Nishida
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  5. Makoto Fujimoto
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  6. Takao Hijikata
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  7. Koichi Tsuneyama
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Corresponding author

Correspondence to Koichi Tsuneyama.

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Animal study

Animal care and surgical procedures were approved by the Institute for Animal Reproduction in accordance with the animal experiment guidelines outlined in the “Principle of laboratory animal care” prepared by the National Academy of Sciences and published by the National Institute of Health (NIH publication no. 85-23 revised 1985).

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All authors declare no conflict of interests.

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Takahashi, T., Deuschle, U., Taira, S. et al. Tsumura-Suzuki obese diabetic mice-derived hepatic tumors closely resemble human hepatocellular carcinomas in metabolism-related genes expression and bile acid accumulation. Hepatol Int 12, 254–261 (2018). https://doi.org/10.1007/s12072-018-9860-3

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  • DOI: https://doi.org/10.1007/s12072-018-9860-3

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