Department of Anatomy and Cell Biology, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, 202-8585, Japan.
Phenex Pharmaceuticals AG, 69123, Heidelberg, Germany.
Hepatol Int. 2018 May;12(3):254-261. doi: 10.1007/s12072-018-9860-3. Epub 2018 Apr 12.
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.
Tsumura-Suzuki 肥胖型糖尿病（TSOD）是一种代谢综合征的良好模型，表现出非酒精性脂肪性肝病和非酒精性脂肪性肝炎中典型的病变，并自发形成高频肝肿瘤。大多数发展中的肿瘤过度表达谷氨酰胺合成酶（GS），GS 被用作肝细胞癌（HCC）的标志物。本研究旨在评估 TSOD 小鼠来源肿瘤中与代谢相关的基因表达状态和胆汁酸水平，并确定人类 HCC 与 TSOD 小鼠来源肿瘤之间代谢失调的关联。
对 71 周龄雄性 TSOD 小鼠的 GS 阳性肝肿瘤或相邻正常组织进行免疫组织化学染色、定量 RT-PCR（qRT-PCR）和胆酸和牛磺胆酸定量。
我们发现，在 GS 阳性的 TSOD 小鼠来源肿瘤中，甜菜碱合成限速酶（BADH）的 mRNA 和蛋白水平均下调。此外，胆汁酸受体 FXR 和胆汁酸排泄泵 BSEP（Abcb11）下调，而 BAAT 和参与初级胆汁酸合成和胆汁酸结合的 Akr1c14 的 mRNA 水平上调。GS 阳性的 TSOD 小鼠来源肿瘤中 BAAT 和 Akr1c14 的蛋白水平也上调。总胆酸在 GS 阳性的 TSOD 小鼠来源肿瘤中增加。
我们的结果强烈支持 TSOD 小鼠作为自发性 HCC 模型的重要性。
