The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.
复制标题
钠-葡萄糖协同转运蛋白 2 抑制剂 Tofogliflozin 在新型小鼠模型中可预防非酒精性脂肪性肝炎相关肝肿瘤的进展。
DOI：
10.1016/j.biopha.2021.111738
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发表时间：
2021
影响因子：
7.5
通讯作者：
Suganami T.
中科院分区：
文献类型：
--
作者：
Yoshioka N;Tanaka M;Ochi K;Watanabe A;Ono K;Sawada M;Ogi T;Itoh M;Ito A;Shiraki Y;Enomoto A;Ishigami M;Fujishiro M;Ogawa Y;Suganami T.
背景糖尿病和肥胖导致非酒精性脂肪性肝炎（NASH）和肝细胞癌（HCC）的发病机制。然而，糖尿病和肥胖如何加速肝脏肿瘤的发生仍有待充分了解。此外，为了验证抗糖尿病药物的治疗潜力，迫切需要能够重现 NASH 和 HCC 人类病理生理学的适当动物模型。方法我们使用基因肥胖的黑皮质素 4 受体缺陷小鼠，结合化学致癌剂喂养，建立了 NASH 相关肝脏肿瘤的新型小鼠模型，并验证了我们的模型在评估药物疗效方面的有效性。 NASH 在相对较短的时间内（大约 3 个月）发生。在此模型中，钠葡萄糖协同转运蛋白 2 抑制剂 Tofogliflozin 阻止了 NASH 样肝脏表型的发展和肝脏肿瘤的进展。 Tofogliflozin 减弱肝脏非肿瘤病变中肝细胞 p21 的表达。解释 Tofogliflozin 治疗可减弱肥胖和糖尿病条件下肝细胞的细胞衰老。该研究提供了一种独特的NASH相关肝脏肿瘤动物模型，适用于评估预防或治疗NASH相关HCC的药物疗效。
BackgroundDiabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC.MethodsWe established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy.FindingsOur model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver.InterpretationTofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.