Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression.
The glucagon-like peptides (GLPs) are synthesized and secreted in a nutrient-dependent manner in rodents; however, the factors regulating human GLP-1 and GLP-2 biosynthesis remain unclear. To understand how nutrients regulate human proglucagon gene expression, we studied the expression of a human proglucagon promoter-growth hormone (GH) transgene in 1.6 human glucagon-GH transgenic mice. Fasting-refeeding significantly decreased and increased the levels of circulating mouse insulin and transgene-derived hGH (P < 0.05 fasting vs. refeeding) and decreased and upregulated, respectively, the levels of endogenous mouse proglucagon RNA in the ileum but not in the jejunum or colon. High-fiber feeding significantly increased the levels of glucose-stimulated circulating hGH and upregulated levels of mouse intestinal proglucagon gene expression in the jejunum, ileum, and colon (P < 0.05, 0 vs. 30% fiber diet). In contrast, neither fasting-refeeding nor a high-fiber diet upregulated the expression of the human proglucagon promoter-hGH transgene. These findings demonstrate that human proglucagon gene regulatory sequences specifying tissue-specific expression in gut endocrine cells are not sufficient for recognition of energy-derived signals regulating murine glucagon gene expression in enteroendocrine cells in vivo.
Nian
Min
M
Department of Laboratory Medicine and Pathobiology, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4.
Gu
Jun
J
Irwin
David M
DM
Drucker
Daniel J
DJ
D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D017931:DNA Primers; D004032:Diet; D004043:Dietary Fiber / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D005934:Glucagon / Q000235:genetics*; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D019382:Human Growth Hormone / Q000097:blood / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D007422:Intestines / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010446:Peptide Fragments / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
D017931:DNA Primers; D004043:Dietary Fiber; D053767:Glucagon-Like Peptide 2; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D019382:Human Growth Hormone; D052216:Glucagon-Like Peptide 1; D005934:Glucagon