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

  • Tetsuyuki Takahashi
  • Ulrich Deuschle
  • Shu Taira
  • Takeshi Nishida
  • Makoto Fujimoto
  • Takao Hijikata
  • Koichi Tsuneyama
Original Article

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.

Keywords

TSOD mice HCC Tumor metabolism Bile acid Spontaneous tumorigenesis model 

Abbreviations

TSOD

Tsumura-Suzuki obese diabetic

GS

Glutamine synthetase

HCC

Hepatocellular carcinoma

IHC

Immunohistochemical staining

qRT-PCR

Quantitative RT-PCR

Notes

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.

Compliance with ethical standards

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).

Conflict of interest

All authors declare no conflict of interests.

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Copyright information

© Asian Pacific Association for the Study of the Liver 2018

Authors and Affiliations

  1. 1.Department of Anatomy and Cell Biology, Faculty of Pharmacy, Research Institute of Pharmaceutical SciencesMusashino UniversityTokyoJapan
  2. 2.Phenex Pharmaceuticals AGHeidelbergGermany
  3. 3.Department of BioscienceFukui Prefectural UniversityFukuiJapan
  4. 4.Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  5. 5.Department of Japanese Oriental Medicine, Graduate School of Medical and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  6. 6.Department of Pathology and Laboratory Medicine, Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan

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