Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis.
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.


CONCLUSIONS
PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect β-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.
Department of Physiology, National Cheng Kung University, 1 University Rd, Tainan 701, Taiwan, Republic of China.
Mun-Wai
MW
Cheong
Li-Hua
LH
Kuo
Yi-Ning
YN
Cheng
Pei-Jane
PJ
Tsai
Li-Chun
LC
Ho
Haw-Chih
HC
Tai
Wen-Tai
WT
Chiu
Shun-Hua
SH
Chen
Pei-Jung
PJ
Lu
Yan-Shen
YS
Shan
Lee-Ming
LM
Chuang
Yau-Sheng
YS
Tsai
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics* / Q000502:physiology; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D010168:Palmitates; D019308:Palmitic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D007328:Insulin; D010168:Palmitates; D034741:RNA, Small Interfering; D019308:Palmitic Acid; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D053148:Caspase 3