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

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

  • Nutrients. 2018 Sep 23;10(10):1366. doi: 10.3390/nu10101366.
Jie Gao 1,  Xin He 2,  Yuejiao Ma 3,  Xuezhi Zhao 4,  Xiaotao Hou 5,  Erwei Hao 6,  Jiagang Deng 7,  Gang Bai 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. [email protected].
  • 2 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. [email protected].
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. [email protected].
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. [email protected].
  • 5 Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning 530200, China. [email protected].
  • 6 Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning 530200, China. [email protected].
  • 7 Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning 530200, China. [email protected].
  • 8 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China. [email protected].
PMID: 30249058 DOI: 10.3390/nu10101366
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 (PIP₃), but directly activated the phosphorylation of Akt on Ser-473, induced the phosphorylation of the downstream molecules, glycogen synthase kinase 3β (GSK3β) 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.

Keywords

chlorogenic acid; forkhead box O1 (FOXO1); glucose metabolism; glycogen synthase kinase 3β (GSK3β); pleckstrin homology (PH) domain; protein kinase B (AKT).

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