Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes
Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes
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发现天然生物碱 Bouchardatine 作为 3T3-L1 脂肪细胞脂肪生成/脂肪生成的新型抑制剂
DOI：
10.1016/j.bmc.2015.05.057
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发表时间：
2015
影响因子：
3.5
通讯作者：
Huang Zhi-Shu
中科院分区：
文献类型：
--
作者：
Rao Yong;Liu Hong;Gao Lin;Yu Hong;Tan Jia-Heng;Ou Tian-Miao;Huang Shi-Liang;Gu Lian-Quan;Ye Ji-Ming;Huang Zhi-Shu
合成了天然存在的β-吲哚喹唑啉生物碱布chardatine(1)。首次研究了1在3T3-L1脂肪细胞中的降脂作用及其机制。我们的研究表明，1能显著降低脂质积累而不产生细胞毒性，主要通过抑制增殖和阻滞细胞周期的剂量依赖性方式抑制脂肪细胞的早期分化。此外，通过下调脂肪生成/脂肪生成的关键调控因子，包括CCAAT增强子结合蛋白（C/EBPβ, C/EBPδ, C/EBPα），过氧化物酶体增殖激活受体γ (PPARγ)和胆固醇调节元件结合蛋白1c （SREBP-1c）的mRNA和蛋白水平，反映了早期分化的抑制。随后还观察到脂肪酸合成限速代谢酶乙酰辅酶A羧化酶（ACC）、脂肪酸合成酶（FAS）和硬脂酰辅酶A去饱和酶1 （SCD-1）蛋白水平的降低。进一步研究发现，1在分化过程中持续激活腺苷5′-单磷酸腺苷（AMP）活化蛋白激酶（AMPK），提示AMPK可能是1影响脂肪形成和脂质形成的上游机制。我们的数据表明，1可以成为开发针对肥胖和相关代谢紊乱的新治疗药物的候选药物。
Bouchardatine (1), a naturally occurring β-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of1was investigated in 3T3-L1 adipocytes. Our study showed that1could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPβ, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that1persistently activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of1on adipogenesis and lipogenesis. Our data suggest that1can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders.