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

Abstract

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.

Alcohol extract of North American ginseng (Panax quinquefolius) reduces fatty liver, dyslipidemia, and other complications of metabolic syndrome in a mouse model

“…Individually, Re is known to exhibit potent antidiabetic effects (Attele et al 2002 ), Rc is antiadipogenic and Rb1 improves insulin signaling and fatty liver by activating AMPK (Shen et al 2013, Shen at al. 2015 and by down-regulating intestinal transport (Wang et al 2015), the effects similar to those observed in the present study.…”

Glucose transporters in the small intestine in health and disease

“…2). For example, binding of hepatic nuclear factor (HNF) 1, transcription factor SP1, and cAMP response element-binding protein (CREB) to the 5′ region of the human SGLT1 gene and their effects on transcription have been demonstrated [259,417]. Employing murine STC-1 cells derived from intestinal endocrine cells, data were obtained which suggest that glucose-induced upregulation of transcription of ovine SGLT1 is dependent on the integrity of the HNF-1 consensus sequence in the promotor [404].…”

Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes

“…A recent clinical study reported that the glycated hemoglobin levels of oral SGLT1 inhibitors were lower than placebo in patients with type 1 diabetes who were receiving insulin (Garg et al, 2017 ). Ginsenoside Rg1, through the regulation of SGLT1 gene expression to effectively reduce intestinal glucose uptake, provides a potential strategy for antihyperglycemia and antidiabetic treatments (Wang et al, 2015a ). Ginsenoside Rg3, F2, compound K, and Rh2 can also inhibit SGLT1 (Gao et al, 2017a ).…”

“…Many studies have reported the antidiabetic activity of ginsenosides. Ginsenosides may improve blood glucose through the regulation of glucose absorption (Shang et al, 2014 ), intervention in glucose transport and/or glucose disposal (Wang et al, 2015a ), and the alteration of insulin secretion and binding (Gu et al, 2013 ). As ginsenosides affect multiple metabolic pathways, their efficacy is complex; furthermore, the various ginsenoside monomer components are difficult to separate.…”