Journal
ENDOCRINOLOGY
Volume 161, Issue 5, Pages -Publisher
ENDOCRINE SOC
DOI: 10.1210/endocr/bqaa039
Keywords
enteroendocrine; exocytosis; GLP-1; glucagon; Munc18-1; SNARE; Stxbp1
Categories
Funding
- Tamarack Graduate Studentship from the Banting and Best Diabetes Centre, University of Toronto
- University of Toronto 'Open' Graduate Studentship
- Canadian Institutes of Health Research (CIHR)
- Banting and Best Diabetes Centre Summer Studentship
- Canada Research Chairs Program
- CIHR [PJT-14853]
- 3D (Digestive Tract and Disease) Centre - Canadian Foundation for Innovation
- Ontario Research Fund [19442, 30961]
- Wellcome Trust [106262/Z/14/Z, 106263/Z/14/Z]
- UK Medical Research Council [MRC_MC_UU_12012/3]
- MRC [MC_UU_00014/5, MC_UU_12012/3, MC_UU_12012/5, MC_UU_00014/3] Funding Source: UKRI
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Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmail1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic alpha- and beta-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion.
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