Egr-1 Deficiency Sensitizes Pancreatic β-Cells to Fatty Acid-Induced ER Stress and Apoptosis

Presentation Number: SUN 604
Date of Presentation: April 2nd, 2017

Yau-Sheng Tsai* and Pei-Jane Tsai
National Cheng Kung University, Tainan, Taiwan

Abstract

Pancreatic β-cells are particularly susceptible to fatty acid-induced ER stress and apoptosis. To understand how β-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which is accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 up-regulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers, and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue β-cells from ER stress and apoptosis through improving insulin/Akt signaling.

 

Nothing to Disclose: YST, PJT