title: An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na+/Glucose Cotransporter 1 Gene Expression.
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.
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Su
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Yu-Chuan
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Fang-Na
authors.initials: FN
authors.lastname: Chan
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Mei-Whey
authors.initials: MW
authors.lastname: Hung
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.).
authors.forename: Hang-Chin
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.). tcchang@ndmctsgh.edu.tw wlchang@ndmctsgh.edu.tw.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chang
authors.affiliation: Graduate Institute of Life Sciences (C.-W.W., T.-C.C.), Department of Biochemistry (S.-C.S., S.-F.H., F.-N.C., Y.-H.K., T.-C.C.), Institute of Preventive Medicine (Y.-C.H.), and School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China (H.-C.L., W.-L.C.); Department of Research and Education, Veteran General Hospital, Taipei, Taiwan, Republic of China (M.-W.H.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-C.C.); and Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-C.C.). tcchang@ndmctsgh.edu.tw wlchang@ndmctsgh.edu.tw.
authors.forename: Tsu-Chung
authors.initials: TC
authors.lastname: Chang
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005786:Gene Expression Regulation; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004365:Drugs, Chinese Herbal; D036145:Ginsenosides; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; C035054:ginsenoside Rg1