title: Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein.
abstract: The glucagon receptor (Gcgr) is essential for maintaining glucose homeostasis in the liver and for stimulating insulin secretion in pancreatic β-cells. Glucose induces rat Gcgr mRNA expression; however, the precise mechanism remains unknown. We previously have studied the role of the carbohydrate response element binding protein (ChREBP), a glucose-activated transcription factor, in the regulation of glucose-stimulated gene expression. The G-box has previously been reported to be responsible for glucose regulation of Gcgr mRNA expression. The G-box comprises two E-boxes separated by 3bp, which distinguishes it from the carbohydrate response element (ChoRE), which has 5-bp spacing between the two E-boxes. In the rat Gcgr promoter, a putative ChoRE (-554bp/-538bp) is localized near the G-box (-543bp/-529bp). In rat INS-1E insulinoma cells, deletion studies of the rat Gcgr promoter show that ChoRE is a minimal glucose response element. Moreover, reporter assays using a pGL3 promoter vector, which harbors ChoRE and chromatin immunoprecipitation assays reveal that ChoRE is a functional glucose response element in the rat Gcgr promoter. Furthermore, In contrast, glucagon partly suppresses glucose-induced expression of Gcgr mRNA. Thus, ChREBP directly regulates rat Gcgr expression in INS-1E cells. In addition, negative feedback looping between ChREBP and GCGR may further contribute to the regulation of glucose-induced gene expression.
authors.affiliation: Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. kiizuka@gifu-u.ac.jp
authors.forename: Katsumi
authors.initials: K
authors.lastname: Iizuka
authors.forename: Reiko
authors.initials: R
authors.lastname: Tomita
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D008156:Luciferases; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C442825:Mlxipl protein, rat; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D005934:Glucagon; D008156:Luciferases; D005947:Glucose