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

Mun Wai Cheong, Li Hua Kuo, Yi Ning Cheng, Pei-Jane Tsai, Li Chun Ho, Haw Chih Tai, Wen-Tai Chiu, Shun-hua Chen, Pei-Jung Lu, Yan-Shen Shan, Lee Ming Chuang, Yau-Sheng Tsai

Research output: Contribution to journalArticle

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Abstract

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: 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.

Original languageEnglish
Pages (from-to)807-818
Number of pages12
JournalJournal of Molecular Medicine
Volume93
Issue number7
DOIs
Publication statusPublished - 2015 Jul 22

Fingerprint

Endoplasmic Reticulum Stress
Palmitates
Palmitic Acid
Apoptosis
Growth
Insulin
Calcium
Fatty Acids
Early Growth Response Protein 1
Phosphorylation
Insulinoma
Survival
Caspase 3
Genes
Cell Differentiation
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

@article{128193d82db14fdab553a148e3c2724b,
title = "Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis",
abstract = "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: 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.",
author = "Cheong, {Mun Wai} and Kuo, {Li Hua} and Cheng, {Yi Ning} and Pei-Jane Tsai and Ho, {Li Chun} and Tai, {Haw Chih} and Wen-Tai Chiu and Shun-hua Chen and Pei-Jung Lu and Yan-Shen Shan and Chuang, {Lee Ming} and Yau-Sheng Tsai",
year = "2015",
month = "7",
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doi = "10.1007/s00109-015-1272-4",
language = "English",
volume = "93",
pages = "807--818",
journal = "Journal of Molecular Medicine",
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Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis. / 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.

In: Journal of Molecular Medicine, Vol. 93, No. 7, 22.07.2015, p. 807-818.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis

AU - Cheong, Mun Wai

AU - Kuo, Li Hua

AU - Cheng, Yi Ning

AU - Tsai, Pei-Jane

AU - Ho, Li Chun

AU - Tai, Haw Chih

AU - Chiu, Wen-Tai

AU - Chen, Shun-hua

AU - Lu, Pei-Jung

AU - Shan, Yan-Shen

AU - Chuang, Lee Ming

AU - Tsai, Yau-Sheng

PY - 2015/7/22

Y1 - 2015/7/22

N2 - 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: 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.

AB - 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: 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.

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