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Title: | Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells |
Author: | Vieira, Elaine Marroquí, Laura Figueroa, Ana Lucia Merino, Beatriz Fernandez-Ruiz, Rebeca Nadal, Angel Burris, Thomas P. Gomis, Ramon, 1946- Quesada, Ivan |
Keywords: | Glucosa Citoquines Genètica humana Pàncrees Glucose Cytokines Human genetics Pancreas |
Issue Date: | 25-Jul-2013 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05) and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold) and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001). High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05). AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01) and glucagon release (p<0.05). These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0069939 |
It is part of: | PLoS One, 2013, vol. 8, num. 7, p. e69939 |
URI: | http://hdl.handle.net/2445/124881 |
Related resource: | https://doi.org/10.1371/journal.pone.0069939 |
ISSN: | 1932-6203 |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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