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Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3?/FOXO1 Signaling and Improves Glucose Metabolism.

ABSTRACT: Chlorogenic acid (CGA), a bioactive component in the human diet, is reported to exert beneficial effects on the regulation of glucose metabolism. This study was designed to investigate the specific target of CGA, and explore its underlying mechanisms. Beneficial effects of CGA in glucose metabolism were confirmed in insulin-treated human hepatocarcinoma HepG2 cells. Protein fishing, via CGA-modified functionalized magnetic microspheres, demonstrated the binding of CGA with protein kinase B (AKT). Immunofluorescence using a CGA molecular probe further demonstrated the co-localization of CGA with AKT. A competitive combination test and hampering of AKT membrane translocation showed that CGA might bind to the pleckstrin homology (PH) domain of AKT. The specific binding did not lead to the membrane translocation to phosphatidylinositol (3,4,5)-trisphosphate (PIP?), but directly activated the phosphorylation of AKT on Ser-473, induced the phosphorylation of the downstream molecules, glycogen synthase kinase 3? (GSK3?) and forkhead box O1 (FOXO1), and improved glucose metabolism. Collectively, our data demonstrate that CGA exerts regulatory effects on glucose metabolism via direct targeting the PH domain of AKT. This study clarifies the mechanism of the potential benefits of nutrients containing CGA in the complementary therapy of glucose metabolism disorders.

SUBMITTER: Gao J

PROVIDER: S-EPMC6212807 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3β/FOXO1 Signaling and Improves Glucose Metabolism.

Gao Jie J He Xin X Ma Yuejiao Y Zhao Xuezhi X Hou Xiaotao X Hao Erwei E Deng Jiagang J Bai Gang G

Nutrients 20180923 10

Chlorogenic acid (CGA), a bioactive component in the human diet, is reported to exert beneficial effects on the regulation of glucose metabolism. This study was designed to investigate the specific target of CGA, and explore its underlying mechanisms. Beneficial effects of CGA in glucose metabolism were confirmed in insulin-treated human hepatocarcinoma HepG2 cells. Protein fishing, via CGA-modified functionalized magnetic microspheres, demonstrated the binding of CGA with protein kinase B (AKT) ...[more]

PMID: 30249058

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Project description:ObjectivePhenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism. It is not clear whether phenolic acids or their metabolites play a major role in vivo. In this study, caffeic acid (CA) and ferulic acid (FA), the two most ingested phenolic acids, and their glucuronic acid metabolites, caffeic-4'-O-glucuronide (CA4G) and ferulic-4'-O-glucuronide (FA4G), were investigated.MethodsThree insulin resistance models in vitro were established by using TNF-α, insulin and palmitic acid (PA) in HepG2 cells, respectively. We compared the effects of FA, FA4G, CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels. The potential targets and related pathways were predicted by network pharmacology. Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target. To investigate the binding mode, molecular docking was performed. Then, we performed membrane recruitment assays of the AKT pleckstrin homology (PH) domain with the help of the PH-GFP plasmid. AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds. Finally, the downstream signaling pathway of AKT was investigated by Western blot analysis.ResultsThe results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption. AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis. The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds. The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site. CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane, while increasing the activity of AKT. Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3β in the AKT signaling pathway to increase glucose consumption.ConclusionIn conclusion, our results suggested that the metabolites of phenolic acids, which contain glucuronic acid, are the key active substances and that they activate AKT by targeting the PH domain, thus improving glucose metabolism.

Dataset Information

Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3?/FOXO1 Signaling and Improves Glucose Metabolism.

Publications

Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3β/FOXO1 Signaling and Improves Glucose Metabolism.

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