Tetsuyuki Takahashi1, Ulrich Deuschle2, Shu Taira3, Takeshi Nishida4, Makoto Fujimoto5, Takao Hijikata1, Koichi Tsuneyama6. 1. Department of Anatomy and Cell Biology, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, 202-8585, Japan. 2. Phenex Pharmaceuticals AG, 69123, Heidelberg, Germany. 3. Department of Bioscience, Fukui Prefectural University, Fukui, 910-1195, Japan. 4. Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. 5. Department of Japanese Oriental Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. 6. Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan. tsuneyama.koichi@tokushima-u.ac.jp.
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.
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.
Authors: Katherine A McGlynn; Kent Hunter; Thomas LeVoyer; Jessica Roush; Philip Wise; Rita A Michielli; Fu-Min Shen; Alison A Evans; W Thomas London; Kenneth H Buetow Journal: Cancer Res Date: 2003-08-01 Impact factor: 12.701
Authors: Serena De Matteis; Andrea Ragusa; Giorgia Marisi; Stefania De Domenico; Andrea Casadei Gardini; Massimiliano Bonafè; Anna Maria Giudetti Journal: Oxid Med Cell Longev Date: 2018-11-04 Impact factor: 6.543