Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Biomed Pharmacother. 2021 Aug;140:111738. doi: 10.1016/j.biopha.2021.111738. Epub 2021 May 21.
Diabetes 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.
We 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.
Our 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.
Tofogliflozin 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.
糖尿病和肥胖是导致非酒精性脂肪性肝炎（NASH）和肝细胞癌（HCC）发病机制的原因。然而，糖尿病和肥胖如何加速肝肿瘤的发生仍未被充分理解。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 人类病理生理学的合适动物模型。
我们使用基因肥胖的黑皮质素 4 受体缺陷小鼠，在西方饮食的基础上结合化学前致癌物，建立了一种新的 NASH 相关肝肿瘤的小鼠模型，并验证了我们的模型在评估药物疗效方面的有效性。
我们的模型在相对较短的时间内（约 3 个月）发展为肥胖、糖尿病和 NASH 相关的多种肝肿瘤。在该模型中，钠-葡萄糖共转运蛋白 2 抑制剂托格列净预防了 NASH 样肝表型的发展和肝肿瘤的进展。托格列净减轻了肝脏非肿瘤病变中肝细胞的 p21 表达。
在肥胖和糖尿病条件下，托格列净治疗可减轻肝细胞的细胞衰老。本研究提供了一种独特的 NASH 相关肝肿瘤动物模型，可用于评估预防或治疗 NASH 相关 HCC 的药物疗效。
