Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan.
Br J Pharmacol. 2020 Jan;177(2):239-253. doi: 10.1111/bph.14859. Epub 2019 Nov 12.
Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis, is closely related to metabolic diseases such as obesity and diabetes. Despite an accumulating number of studies, no pharmacotherapy that targets NAFLD has received general approval for clinical use.
Inhibition of the sodium-glucose cotransporter 2 (SGLT2) is a promising approach to treat diabetes, obesity, and associated metabolic disorders. In this study, we investigated the effect of a novel SGLT2 inhibitor, NGI001, on NAFLD and obesity-associated metabolic symptoms in high-fat diet (HFD)-induced obese mice.
Delayed intervention with NGI001 protected against body weight gain, hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, compared with HFD alone. Adipocyte hypertrophy was prevented by administering NGI001. NGI001 inhibited impaired glucose metabolism and regulated the secretion of adipokines associated with insulin resistance. In addition, NGI001 supplementation suppressed hepatic lipid accumulation and inflammation but had little effect on kidney function. In-depth investigations showed that NGI001 ameliorated fat deposition and increased AMPK phosphorylation, resulting in phosphorylation of its major downstream target, acetyl-CoA carboxylase, in human hepatocyte HuS-E/2 cells. This cascade ultimately led to the down-regulation of downstream fatty acid synthesis-related molecules and the up-regulation of downstream β oxidation-associated molecules. Surprisingly, NGI001 decreased gene and protein expression of SGLT1 and SGLT2 and glucose uptake in oleic acid-treated HuS-E/2 cells.
Our findings suggest the novel SGLT2 inhibitor, NGI001 has therapeutic potential to attenuate or delay the onset of diet-induced metabolic diseases and NAFLD.
非酒精性脂肪性肝病（NAFLD），包括非酒精性脂肪性肝炎，与肥胖症和糖尿病等代谢性疾病密切相关。尽管研究数量不断增加，但没有一种针对 NAFLD 的药物疗法被普遍批准用于临床。
抑制钠-葡萄糖共转运蛋白 2（SGLT2）是治疗糖尿病、肥胖症和相关代谢紊乱的一种很有前途的方法。在这项研究中，我们研究了一种新型 SGLT2 抑制剂 NGI001 对高脂肪饮食（HFD）诱导肥胖小鼠的 NAFLD 和肥胖相关代谢症状的影响。
与单独 HFD 相比，延迟干预 NGI001 可防止体重增加、高血糖、高血脂和高胰岛素血症。给予 NGI001 可防止脂肪细胞肥大。NGI001 抑制受损的葡萄糖代谢并调节与胰岛素抵抗相关的脂肪因子的分泌。此外，NGI001 补充剂抑制肝脂质积累和炎症，但对肾功能影响不大。深入研究表明，NGI001 改善脂肪沉积并增加 AMPK 磷酸化，导致其主要下游靶标乙酰辅酶 A 羧化酶磷酸化，在人肝细胞 HuS-E/2 细胞中。这一级联反应最终导致下游脂肪酸合成相关分子下调和下游β氧化相关分子上调。令人惊讶的是，NGI001 降低了油酸处理的 HuS-E/2 细胞中 SGLT1 和 SGLT2 的基因和蛋白表达以及葡萄糖摄取。
我们的研究结果表明，新型 SGLT2 抑制剂 NGI001 具有治疗潜力，可以减轻或延迟饮食引起的代谢性疾病和 NAFLD 的发生。
