Malabaricone C as Natural Sphingomyelin Synthase Inhibitor against Diet-Induced Obesity and Its Lipid Metabolism in Mice
Malabaricone C as Natural Sphingomyelin Synthase Inhibitor against Diet-Induced Obesity and Its Lipid Metabolism in Mice
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DOI：
10.1021/acsmedchemlett.9b00171
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发表时间：
2019-08-01
影响因子：
4.2
通讯作者：
Monde, Kenji
中科院分区：
文献类型：
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作者：
Othman, Muhamad Aqmal;Yuyama, Kohei;Monde, Kenji
天然存在的抑制剂和靶向膜蛋白之间的相互作用可能是治疗代谢综合征，特别是肥胖的替代药物策略。在这项研究中，我们从肉豆蔻（Myristica cinnamomea King）的果实中分离到malabaricones a - c和E（1-4）作为鞘磷脂合成酶（sphingomyelin synthase， SMS）的天然抑制剂，SMS是一种负责鞘脂生物合成的膜蛋白。在高脂饮食诱导的肥胖小鼠模型中，口服化合物3在减少体重增加、改善葡萄糖耐量和减少肝脏脂肪变性方面表现出多种功效，具有最有希望的抑制作用。肝脏脂质分析揭示了化合物3的SMS活性与其体内和体外脂质代谢之间的重要联系。化合物3的无毒特性使其成为治疗和预防肥胖药物的合适候选物。
The interaction between natural occurring inhibitors and targeted membrane proteins could be an alternative medicinal strategy for the treatment of metabolic syndrome, notably, obesity. In this study, we identified malabaricones A-C and E (1-4) isolated from the fruits of Myristica cinnamomea King as natural inhibitors for sphingomyelin synthase (SMS), a membrane protein responsible for sphingolipid biosynthesis. Having the most promising inhibition, oral administration of compound 3 exhibited multiple efficacies in reducing weight gain, improving glucose tolerance, and reducing hepatic steatosis in high fat diet-induced obesity mice models. Liver lipid analysis revealed a crucial link between the SMS activities of compound 3 and its lipid metabolism in vitro and in vivo. The nontoxic nature of compound 3 makes it a suitable candidate in search of drugs which can be employed in the treatment and prevention of obesity.