Tsumura-Suzuki obese diabetic mice-derived hepatic tumors closely resemble human hepatocellular carcinomas in metabolism-related genes expression and bile acid accumulation
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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DOI：
10.1007/s12072-018-9860-3
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发表时间：
2018-05-01
影响因子：
6.6
通讯作者：
Tsuneyama, Koichi
中科院分区：
文献类型：
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作者：
Takahashi, Tetsuyuki;Deuschle, Ulrich;Tsuneyama, Koichi
津村-铃木肥胖糖尿病（TSOD）是代谢综合征的良好模型，表现出非酒精性脂肪肝病和非酒精性脂肪性肝炎中的典型病变，并且高频率地发生自发性肝肿瘤。大多数正在发育的肿瘤过度表达谷氨酰胺合成酶（GS），谷氨酰胺合成酶被用作肝细胞癌（HCC）的标志物。本研究的目的是评估 TSOD 小鼠源性肿瘤中代谢相关基因的表达状况和胆汁酸水平，并确定人类 HCC 和 TSOD 小鼠源性肿瘤之间代谢失调的关系。对 71 周龄雄性 TSOD 小鼠的 GS 阳性肝肿瘤或邻近正常组织进行免疫组化染色、定量分析。 RT-PCR (qRT-PCR)，胆酸和牛磺胆酸的定量。我们发现，在 GS 阳性 TSOD 小鼠来源的肿瘤中，甜菜碱合成限速酶 (BADH) 在 mRNA 和蛋白质水平上均下调。此外，在 GS 阳性 TSOD 小鼠来源的肿瘤中，胆汁酸受体 FXR 和胆汁酸排泄泵 BSEP (Abcb11) 下调，而参与初级胆汁酸合成和胆汁酸结合的 BAAT 和 Akr1c14 在 mRNA 水平上调。 BAAT 和 Akr1c14 在蛋白质水平上也过度表达。发现 GS 阳性 TSOD 小鼠来源的肿瘤中总胆酸增加。我们的结果强烈支持 TSOD 小鼠作为自发发展的 HCC 模型的重要性。
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.