In this study, we measured the effect of ginsenosides on glucose uptake using the Caco-2 cell system. At submicromolar concentrations, these compounds exhibited marked effects on the rate of glucose transport across the differentiated Caco-2 cell monolayer. Compound K (CK), the main intestinal bacterial metabolite of the protopanaxadiol ginsenosides, significantly enhanced the steady-state glucose transport rate to about 50% of the control sample rate (from 1.54 +/- 0.09 to 2.25 +/- 0.15 nmol/min). Conversely, the protopanaxatriol ginsenoside Rg1 inhibited glucose transport to about 70% of the original rate (from 1.54 +/- 0.09 to 1.02 +/- 0.05 nmol/min). Consistent with the effect on glucose uptake rate, CK and Rg1 conferred a significant and paralleled alteration on both the protein and mRNA expression levels of the Na+/glucose cotransporter 1 (SGLT1) gene. Unlike SGLT1, there is no significant alteration on the protein or mRNA levels of GLUTs in CK- or Rg1-treated cells. Taken together, our results demonstrate that ginsenosides CK and Rg1 elicited potent enhancing and suppressing effects, respectively, on glucose uptake across human intestinal Caco-2 monolayer through modulation of SGLT1 expression.
The Na 1 /glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. It has been shown that the intestinal SGLT1 level is significantly increased in diabetic individuals and positively correlated with the pathogenesis of diabetes. The development of targeted therapeutics that can reduce the intestinal SGLT1 expression level is, therefore, important. In this study, we showed that ginsenoside Rg1 effectively decreased intestinal glucose uptake through inhibition of SGLT1 gene expression in vivo and in vitro. Transient transfection analysis of the SGLT1 promoter revealed an essential cAMP response element (CRE) that confers the Rg1-mediated inhibition of SGLT1 gene expression. Chromatin immunoprecipitation assay and targeted CRE-binding protein (CREB) silencing demonstrated that Rg1 reduced the promoter binding of CREB and CREB binding protein associated with an inactivated chromatin status. In addition, further studies showed that the epidermal growth factor receptor (EGFR) signaling pathway also plays an essential role in the inhibitory effect of Rg1; taken together, our study demonstrates the involvement of the EGFR-CREB signaling pathway in the Rg1-mediated downregulation of SGLT1 expression, which offers a potential strategy in the development of antihyperglycemic and antidiabetic treatments.
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.
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