Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH)
Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH)
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DOI：
10.1002/2211-5463.12598
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发表时间：
2019-04-01
期刊：
影响因子：
2.6
通讯作者：
Terai, Shuji
中科院分区：
文献类型：
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作者：
Goto, Ryo;Kamimura, Kenya;Terai, Shuji
非酒精性脂肪性肝炎（NASH）发病率的上升需要开发有效的预防方法。已检测了一种属于钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂组的降糖药物对NASH的治疗作用;然而，迄今为止，尚无研究证明SGLT 2抑制剂在动物模型中以序贯方式对脂肪变性和纤维化的组织学进展具有预防作用。在本研究中，我们使用青鳉作为动物模型，在所有动物体内维持摄食量和药物浓度，检查SGLT 2抑制剂托佛格列汀（Tofo）对NASH肝组织的影响。我们通过给d-rR/东京青鳉喂食高脂肪饮食产生青鳉NASH模型，并通过将药物直接溶解在饲养罐的水中来施用Tofo。此后，检查了Tofo对体重（BW）、肝脏重量、肝毒性、脂肪浸润和肝脏纤维化变化的影响。我们在此报告，SGLT 2在青鳉鱼中表达，Tofo通过抑制血糖、血脂和转氨酶的升高，抑制脂肪组织的积累，并延缓青鳉NASH模型中肝纤维化的进展，而与BW的变化无关。这些结果表明，Tofo对治疗NASH是有效的，青鳉模型可能有助于开发这种疾病的新治疗药物。
The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d-rR/Tokyo medaka a high-fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.