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.


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).

MeSH terms

  • Blood Glucose / metabolism*
  • Chlorogenic Acid / pharmacology*
  • Diet
  • Forkhead Box Protein O1 / metabolism*
  • Glucose / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Resistance
  • Magnetics
  • Membranes / metabolism
  • Microspheres
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphorylation
  • Plant Extracts / pharmacology*
  • Pleckstrin Homology Domains*
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction


  • Blood Glucose
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Insulin
  • Phosphatidylinositol Phosphates
  • Plant Extracts
  • phosphatidylinositol 3,4,5-triphosphate
  • Chlorogenic Acid
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glucose