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

Mol Pharmacol. 2015 Dec;88(6):1072-83. doi: 10.1124/mol.114.097352. Epub 2015 Oct 1.

Abstract

The Na(+)/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Drugs, Chinese Herbal / pharmacology*
  • Gene Expression Regulation
  • Ginsenosides / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sodium-Glucose Transporter 1 / antagonists & inhibitors*
  • Sodium-Glucose Transporter 1 / biosynthesis*

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Drugs, Chinese Herbal
  • Ginsenosides
  • SLC5A1 protein, human
  • Sodium-Glucose Transporter 1
  • ginsenoside Rg1