Screening of Isoquinoline Alkaloids for Potent Lipid Metabolism Modulation with Caenorhabditis elegans
Screening of Isoquinoline Alkaloids for Potent Lipid Metabolism Modulation with Caenorhabditis elegans
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DOI：
10.1271/bbb.130523
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发表时间：
2013-12-01
影响因子：
1.6
通讯作者：
Sato, Fumihiko
中科院分区：
文献类型：
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作者：
Chow, Yit-Lai;Sato, Fumihiko
代谢综合征和相关疾病在当代社会日益普遍，因此需要有效的药物来控制体内的脂质积累。本研究表明，秀丽隐杆线虫以黄连素为模型化合物，可有效地筛选出有效的脂代谢调节剂。在所测试的各种异喹啉生物碱中，血根碱被发现是最有效的。血根碱和黄连素一样，通过激活AMP激活的蛋白激酶来减少脂肪堆积。对AMPK(AAK-1和AAK-2)RNAi蠕虫的分析表明，这种作用是AAK-2依赖的。对带有NHR-49(一种荷尔蒙核受体基因，对脂肪消耗起关键调节作用)的蠕虫的表征表明，这两种生物碱即使在这些明显积累脂肪的NHR-49 RNAi蠕虫中也是有效的，这表明它们主要影响脂质合成，而不是脂肪酸β氧化。讨论了秀丽线虫在调脂化学筛选和潜在机制表征方面的多样性。
Metabolic syndrome and related disorders are increasingly prevalent in contemporary society, and thus pose the need for potent agents to control lipid accumulation in the body. This study indicates that Caenorhabditis elegans was effective in screening for potent lipid metabolism modulators with berberine as a model compound. Among the various isoquinoline alkaloids tested, sanguinarine, a benzophenanthridine alkaloid, was found to be the most potent. Sanguinarine, like berberine, reduced lipid accumulation through AMP-activated protein kinase activation. Analysis of AMPK (aak-1 and aak-2) RNAi worms revealed that effects were aak-2-dependent. Characterization of worms with knockdown nhr-49, a hormone nuclear receptor gene that functions as a key regulator of fat consumption, showed that both alkaloids were effective even in these markedly lipid-accumulating nhr-49 RNAi worms, suggesting that they predominantly affect lipid synthesis, rather than fatty acid beta-oxidation. The versatility of C. elegans for the purpose of lipid-modulating chemical screening and characterization of the underlying mechanisms is discussed.