Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3β/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 (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.

Angiotensin‐(1‐7), the product of ACE2 ameliorates NAFLD by acting through its receptor Mas to regulate hepatic mitochondrial function and glycolipid metabolism

“…To enhance our understanding of the increased IR in Mas ‐/‐ mice, we examined the expression of glucose‐metabolism‐related proteins in the liver. GSK3β is considered to interact with FOXO1 to regulate gluconeogenesis 14 . In the present study, phospho‐FOXO1 and phospho‐GSK3β levels were decreased in Mas −/− mice and mirrored the markedly increased expression of G6Pase and PEPCK (Figure 1L), the critical rate‐limiting enzymes in the gluconeogenic pathway.…”

“…GSK3β is considered to interact with FOXO1 to regulate gluconeogenesis. 14 In the present study, phospho-FOXO1 and phospho-GSK3β levels were decreased in Mas −/− mice and mirrored the markedly increased expression of G6Pase and PEPCK ( Figure 1L), the critical rate-limiting enzymes in the gluconeogenic pathway. In terms of fatty acid metabolism, Mas −/− mice showed a significant increase in FAS, the key enzyme required for TG synthesis, and a slight increase in ACCα, but showed a notable decrease in ATGL, a rate-limiting enzyme in TG metabolism, and no change in phospho-HSL ( Figure 1M).…”

A Randomized Crossover Intervention Study on the Effect a Standardized Maté Extract (Ilex paraguariensis A. St.-Hil.) in Men Predisposed to Cardiovascular Risk

“…The effects of CGAs have been related to an inhibition of carbohydrate digestion by inhibiting amylase [ 30 , 31 ], to the preventing action of glycosidase in the brush border of the small intestine [ 32 ], to modulation of gastrointestinal peptides shifting glucose absorption to more distal region in the GI tract [ 10 ] and also to a reduction of hepatic glucose output [ 33 ]. Recent investigations have suggested that CGA could regulate glucose metabolism by directly interacting with the AKT (protein kinase B) related pathway, leading to glycogen synthase activation and lowering blood glucose [ 34 ]. Based on this literature, we aimed to evaluate the impact of a nutritional intake of CQAs from maté extract on glycemic control in humans.…”

Lepidiline A Improves the Balance of Endogenous Sex Hormones and Increases Fecundity by Targeting HSD17B1

“…Proteins were then extracted and quantified according to a previously reported method. [ 42 ] Protein lysates were treated with LA‐modified MMs (as shown in Figure S3, Supporting Information) and incubated overnight at 4 °C to capture the target protein. The MMs were magnetically separated and washed with PBS.…”