A gut microbial metabolite of ginsenosides, compound K, induces intestinal glucose absorption and Na⁺/glucose cotransporter 1 gene expression through activation of cAMP response element binding protein

Abstract

Scope:The Na + /glucose cotransporter 1 (SGLT1) plays a crucial role in glucose uptake in intestinal epithelial cells (IECs), which has been shown essential in ameliorating intestinal inflammation. Ginseng has historically been used to treat inflammatory disorders. Understanding the regulatory mechanism of ginseng-mediated induction of SGLT1 gene expression in human intestinal cells is therefore important. Methods and results:We demonstrate that ginsenoside compound K (CK) enhances SGLT1-mediated glucose uptake in mice and human intestinal Caco-2 cells. Transient transfection analysis using SGLT1 promoter-luciferase reporters demonstrated that the presence of an essential cAMP response element (CRE) is required for CK-mediated induction of SGLT1 gene expression. The ChIP assays indicated that increased CRE-binding protein (CREB) and CREBbinding protein (CBP) binding to the SGLT1 promoter in CK-treated cells is associated with an activated chromatin state. Our result showed that the increased CREB phosphorylation is directly correlated with SGLT1 expression in IECs. Further studies indicated that the epidermal growth factor receptor (EGFR) signaling pathway is involved in the CK-mediated effect. Conclusion: These findings provide a novel mechanism for the CK-mediated upregulation of SGLT1 expression through EGFR-CREB signaling activation, which could contribute to reducing gut inflammation.

<p>SLC5A1 promotes growth and proliferation of pancreatic carcinoma via glucose-dependent AMPK/mTOR signaling</p>

“…Indeed, attempts to suppress cancer cells by targeting this protein pair have been made. It was found that some compounds from a natural anti-cancer medicinal plant Panax ginseng concurrently suppressed EGFR and SGLT1 in a CREB-associated mechanism 40,41. Co-inhibition of EGFR and SGLT1 obtained an optimal outcome in suppressing prostate cancer compared with EGFR inhibitor alone.…”

Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities

“…In addition, the use of CK as BSA-CK NPs [ 39 ] and CK-conjugated superparamagnetic iron oxide nanoparticles [ 58 ], has been shown to have anti-inflammatory activity against RAW 264.7 cells induced by LPS. In another study, CK-mediated modulation of sodium/glucose cotransporter one via the epidermal growth factor receptor (EGFR) pathway was found to reduce intestinal inflammation [ 59 ].…”

An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na+/Glucose Cotransporter 1 Gene Expression

“…The sequences of DNA primers for PCR are listed in Table 1. Subsequently, serial 59-deletions and site mutations of the SGLT1 promoter were generated by PCR to obtain the SGLT1 (21560/122), (2500/122), (2235/122), (2169/122), (2136/122), (283/122), (227/122), and (mutant CRE) luciferase reporter plasmids as previously described (Martin et al, 2000;Wang et al, 2015). The sequence and orientation of the individual luciferase reporter constructs were confirmed by restriction mapping and DNA sequence analysis.…”