Discovery of lignans as the effective inhibitors of CES1A alleviate lipid droplets formation.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jie Mu, Si-Si Chen, Shi-Qing Li, Qiang Jin, Jin Geng, Li-Wei Zou
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引用次数: 0

Abstract

ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.

木脂素作为CES1A有效抑制剂的发现减轻了脂滴的形成。
内质网羧酸酯酶1A (CES1A)是参与脂质代谢的重要代谢酶。靶向CES1A是治疗脂质代谢紊乱相关疾病的一种很有前景的方法。在本研究中,筛选了26种天然木脂素,发现其中3种对CES1A具有强抑制作用,并且对其他丝氨酸水解酶具有高特异性。抑制动力学分析表明,五味子素C和安五里甘为混合型抑制剂,厚朴酚为竞争性抑制剂。进一步的研究表明,它们具有细胞渗透性,表现出最小的细胞毒性和线粒体毒性,并且能够抑制活细胞内的CES1A。进一步研究发现,三种五味子可降低游离脂肪酸(FFA)处理HepG2细胞的脂滴(ld)数量。总之,我们的研究结果表明,五味子素C是一种有效的、高选择性的CES1A抑制剂,可以作为一种有前途的先导化合物。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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