التفاصيل البيبلوغرافية
| العنوان: |
Involvement of the Clock Gene Rev-erb alpha in the Regulation of Glucagon Secretion in Pancreatic Alpha-Cells. |
| المؤلفون: |
Vieira, Elaine1,2 evieira@ciberdem.org, Marroquí, Laura1,2, Figueroa, Ana Lucia C.3, Merino, Beatriz1,2, Fernandez-Ruiz, Rebeca2,3, Nadal, Angel1,2, Burris, Thomas P.4, Gomis, Ramon2,3,5, Quesada, Ivan1,2 ivanq@umh.es |
| المصدر: |
PLoS ONE. Jul2013, Vol. 8 Issue 7, p1-15. 15p. |
| مصطلحات موضوعية: |
*MOLECULAR clock, *GLUCAGON regulation, *ISLANDS of Langerhans, *PANCREATIC beta cells, *GENETICS of diabetes, *SMALL interfering RNA |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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