Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice.
Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice.
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DOI：
10.18632/oncotarget.16874
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Shimizu M
中科院分区：
文献类型：
--
作者：
Obara K;Shirakami Y;Maruta A;Ideta T;Miyazaki T;Kochi T;Sakai H;Tanaka T;Seishima M;Shimizu M
钠葡萄糖协同转运蛋白2抑制剂有望改善与代谢综合征相关的异常，包括非酒精性脂肪肝。在这项研究中，我们研究了钠-葡萄糖协同转运蛋白2抑制剂tofoglilidine对C57 BL/KsJ-+Leprdb/+Leprdb肥胖和糖尿病小鼠非酒精性脂肪性肝病相关肝脏肿瘤发生的影响。还评价了托福格列净对人肝癌细胞增殖的直接影响。小鼠给予含二乙基亚硝胺的水2周，并在整个实验期间用托福格列净治疗。与对照小鼠相比，使用非酒精性脂肪肝疾病活动评分评价，托福格列净治疗的小鼠肝脏癌前病变的发展明显受到抑制，肝脏脂肪变性和炎症显著减少。托福格列净治疗降低了葡萄糖和游离脂肪酸的血清水平以及肝脏中促炎标志物的mRNA表达水平。相反，钠葡萄糖协同转运蛋白2蛋白表达的肝癌细胞的增殖并没有受到这种药物的抑制。这些结果表明，托福格列净通过减轻慢性炎症和肝脏脂肪变性抑制肥胖和非酒精性脂肪肝相关肝癌发生的早期阶段。因此，钠葡萄糖协同转运蛋白2抑制剂可能对肥胖相关的肝细胞癌具有化学预防作用。
Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.
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影响因子：
--
作者：
Miyazaki T;Shirakami Y;Kubota M;Ideta T;Kochi T;Sakai H;Tanaka T;Moriwaki H;Shimizu M
通讯作者：
Shimizu M
影响因子：
3
作者：
Fonseca, Vivian A.;Ferrannini, Ele;Klasen, Sally
通讯作者：
Klasen, Sally
影响因子：
6.7
作者：
Park, E. K.;Jung, H. S.;Kim, K. S.
通讯作者：
Kim, K. S.
影响因子：
3.7
作者：
Ohno T;Shimizu M;Shirakami Y;Baba A;Kochi T;Kubota M;Tsurumi H;Tanaka T;Moriwaki H
通讯作者：
Moriwaki H
影响因子：
5.1
作者：
Du, Shanshan;Wang, Cheng;Sun, Changhao
通讯作者：
Sun, Changhao