Screening of isoquinoline alkaloids for potent lipid metabolism modulation with Caenorhabditis elegans

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 β-oxidation. The versatility of C. elegans for the purpose of lipid-modulating chemical screening and characterization of the underlying mechanisms is discussed.