We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis.
- Authors
Cheong, Mun-Wai; Kuo, Li-Hua; Cheng, Yi-Ning; Tsai, Pei-Jane; Ho, Li-Chun; Tai, Haw-Chih; Chiu, Wen-Tai; Chen, Shun-Hua; Lu, Pei-Jung; Shan, Yan-Shen; Chuang, Lee-Ming; Tsai, Yau-Sheng
- Abstract
Pancreatic β-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (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 and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, 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. Our study underscores Egr-1 as a critical early sensor in pancreatic β-cells to translate fatty acid stimuli into a cellular adaptation mechanism. Key Message:
- Subjects
IMMEDIATE-early genes; TRANSCRIPTION factors; ENDOPLASMIC reticulum; INSULIN; PANCREATIC beta cells; APOPTOSIS
- Publication
Journal of Molecular Medicine, 2015, Vol 93, Issue 7, p807
- ISSN
0946-2716
- Publication type
Article
- DOI
10.1007/s00109-015-1272-4