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

Abstract

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