Phenolic acids widely exist in human diet, of which caffeic acid (CA) and ferulic acid (FA) are the most ingested. Whether the phenolic acids or their metabolisms play a regulatory role in vivo is a topic worth exploring. In this paper, CA, FA and their glucuronic acid metabolites, caffeic-4'-O-glucuronide (CA4G) and ferulic-4'-O-glucuronide (FA4G), were evaluated the capacity in increasing glucose consumption. The result showed that CA4G and FA4G exerted more potent effect than their parent compounds. Molecular docking indicated the possible binding of carbonyl group in glucuronic acid structure of CA4G and FA4G with the pleckstrin homology (PH) domain of AKT at a key Arg-25 site. The fluorescence quenching test confirmed the more potent binding exerted by the two metabolites. They inhibited the recruitment of AKT PH domain to the membrane, meanwhile increased the activity of AKT. Western blot demonstrated that the metabolites could increase the phosphorylation of downstream glycogen synthase kinase 3β of AKT signaling pathway to increase glucose consumption. The result brings us to a new realization that the metabolites of phenolic acids, which contain glucuronic acid, are the key active substances. They activate AKT by targeting the PH domain, thus improving glucose metabolism.

中文翻译：

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酚酸的葡萄糖醛酸代谢产物通过靶向AKT-PH结构域改善葡萄糖代谢

人体饮食中广泛存在酚酸，其中摄入最多的是咖啡酸（CA）和阿魏酸（FA）。酚酸或其代谢在体内是否起调节作用是一个值得探讨的话题。在本文中，评估了CA，FA及其葡萄糖醛酸代谢产物咖啡因4'-O-葡糖醛酸（CA4G）和阿魏酸4'-O-葡糖醛酸（FA4G）的增加葡萄糖消耗的能力。结果表明，CA4G和FA4G的作用比其母体化合物强。分子对接表明CA4G和FA4G的葡萄糖醛酸结构中的羰基可能与关键的Arg-25位点的AKT的pleckstrin同源性（PH）域结合。荧光猝灭测试证实了两种代谢物产生的更有效的结合。它们抑制了AKT PH结构域向膜的募集，同时增加了AKT的活性。Western印迹表明，代谢产物可以增加AKT信号通路下游糖原合酶激酶3β的磷酸化，从而增加葡萄糖消耗。结果使我们重新认识到，包含葡萄糖醛酸的酚酸代谢物是关键的活性物质。它们通过靶向PH结构域来激活AKT，从而改善葡萄糖代谢。是关键的活性物质。它们通过靶向PH结构域来激活AKT，从而改善葡萄糖代谢。是关键的活性物质。它们通过靶向PH结构域来激活AKT，从而改善葡萄糖代谢。