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系統識別號 U0026-2908201321233500
論文名稱(中文) Egr1保護胰島beta細胞免於受到游離脂肪酸引起之細胞凋亡
論文名稱(英文) Early growth response-1 protects pancreatic beta-cells from free fatty acid-induced apoptosis
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 101
學期 2
出版年 102
研究生(中文) 張文維
研究生(英文) Mun-Wai Cheong
學號 S36971112
學位類別 碩士
語文別 英文
論文頁數 50頁
口試委員 指導教授-蔡曜聲
口試委員-呂佩融
口試委員-陳舜華
口試委員-沈延盛
中文關鍵字 早期生長反應蛋白  胰島beta細胞  游離脂肪酸  細胞凋亡 
英文關鍵字 early growth response-1  pancreatic beta cell  free fatty acid  endoplasmic reticulum stress  apoptosis 
學科別分類
中文摘要 早期生長反應蛋白(Early growth response-1)為一種鋅手指轉錄調控因子,其表現會受到許多週邊環境刺激的影響,目前已知能夠調控許多基因表現,包括細胞分化、生長以及細胞凋亡。在胰島的beta細胞中,早期生長反應蛋白會因為葡糖糖的刺激進而協助調控胰島素的生成。胰島中的beta細胞在葡萄糖的代謝上扮演重要角色,beta細胞的缺失與糖尿病的病變息息相關。早前,我們實驗室發現早期生長反應蛋白基因剔除老鼠在餵食高脂肪飼料 (high fat diet)後,胰島的面積以及數量會有減少的現象。因此,我們假設在游離脂肪酸作用下會誘使beta細胞內的早期生長反應蛋白產生,並且可以減輕游離脂肪酸引起beta細胞凋亡。棕梠酸是循環系統中占最大比例的游離脂肪酸。給予棕梠酸刺激以後,MIN6胰島細胞會在60分鐘內產生早期生長反應蛋白。若額外給予鈣離子螯合劑(EGTA)或L型鈣離子通道抑制劑 (nifepidine)可以抑制棕梠酸誘使早期生長反應蛋白產生。此外,我們發現棕梠酸可以刺激細胞內的ERK1/2發生磷酸化,一旦抑制ERK1/2磷酸化則會減少棕梠酸誘使早期生長反應蛋白產生。實驗結果證明,在棕梠酸的刺激下會使細胞發生鈣離子內流(Ca2+ influx)以及ERK1/2磷酸化,進而使得早期生長反應蛋白表現增加。另一方面,我們發現早期生長反應蛋白基因剔除的細胞更容易受棕梠酸影響加劇內質網壓力(ER stress)以及caspase 3活化導致發生細胞凋亡。在這過程中,早期生長反應蛋白基因剔除的beta細胞有較少的Akt磷酸化,這意味著缺少早期生長反應蛋白會降低PI3K/Akt存活路徑。在此同時,我們發早期生長反應蛋白基因剔除的細胞產生較少的胰島素mRNA,可是卻不會影響胰島素的分泌。此外,額外補充胰島素可以減輕早期生長反應蛋白基因剔除的beta細胞因棕梠酸引起的細胞凋亡。總結以上結果,早期生長反應蛋白會受棕梠酸刺激而產生,進而保護beta細胞避免棕梠酸引起細胞凋亡及加強胰島素的訊息傳遞。這證實了早期生長反應蛋白在胰島細胞扮演其他功能並保護系保免於受到游離脂肪酸引起細胞凋亡。
英文摘要 Early growth response-1 (Egr1), a zinc-finger DNA binding transcription factor, is induced by many environmental signals and is highly associated with cell differentiation, proliferation and apoptosis. In the pancreatic islet, Egr1 mediates responses of pancreatic beta cells to sustained glucose stimulation and regulates insulin production. Pancreatic beta cell plays a crucial role in glucose homeostasis and its failure is related to diabetes mellitus. Previously, our lab revealed that mean islet area and number decreased in high-fat-fed Egr1 knockout mice. Thus, we hypothesized that Egr1 is increased in response to FFA to attenuate FFA-induced apoptosis in pancreatic beta cells. In this study, we used MIN6 insulinoma cells and treated with palmitic acid (PA), the most abundant FFA in circulation. Our data revealed that Egr1 was induced within 2 hours by PA in MIN6 cells. Treatment of EGTA (calcium chelator) or nifepidine (L-type calcium channel inhibitor) blocked PA-induced Egr1 upregulation. Moreover, we found increased phosphorylation of ERK1/2 after treatment of PA, and PA-induced Egr1 upregulation was attenuated by ERK1/2 inhibitor. These results suggest that PA induces Egr1 expression through Ca2+ influx and ERK1/2 activation. Next, we found that Egr1-knockdown cells were more susceptible to PA-induced caspase 3 activation and increased the level of pro-apoptotic ER stress marker, CHOP. Furthermore, Akt phosphorylation in Egr1 knockdown cells was decreased, suggesting that the absence of Egr1 downregulates the PI3K/Akt survival pathway. Meanwhile, we found that Egr1 knockdown cells decreased insulin mRNA but did not affect insulin secretion under PA treatment. Finally, Egr1 knockdown impaired insulin signal transduction, and insulin supplementation rescued PA-induce apoptosis in Egr1 knockdown cells. In conclusion, our data showed that Egr1 is induced by PA and further attempts to rescue beta cells from PA-induced apoptosis through improving insulin signaling pathway. This study demonstrates other functions of Egr1 in pancreatic beta cells and provides a candidate to protect from beta cell failure.
論文目次 INTRODUCTION.............1
beta cell death in diabetes............1
Free fatty acid toxicity in cells..........2
ER stress in cells.............2
Survival and death signaling pathway incells.......3
FFA modulates insulin production and secretion.......4
Early growth response-1 (Egr1)..........5
Function of Egr1.............5
Induction of Egr1............6
Function of Egr1 in pancreatic cell........7
Significance............7
MATERIALS AND METHODS..........8
Cell culture and palmitic acid (PA) treatment.......8
Freezing cells............8
Protein extraction............9
Western blotting............9
Insulin secretion and ELISA assay........10
Cell RNA extraction............10
Real-time PCR.............11
Immunoflourecence...........11
shRNA lentivirus production..........12
Lentivirus infection...........12
Transfection.............12
Data analysis.............13
RESULTS.............14
Free fatty acid induced Egr1 expression in MIN6 insulinoma pancreatic cells..14
PA-induced Egr1 expression required calcium influx......14
ERK1/2 activation was involved in PA-induced Egr1 expression...15
Egr1 attenuated PA-induced apoptosis.........16
Egr1 alleviated ER stress..........16
Egr1 knockdown decreased the PI3K/Akt survival pathway....17
Insulin supplementation rescued PA-induced apoptosis.....18
Egr1 knockdown impaired insulin signaling pathway......19
DISCUSSION............20
REFERENCES............27
TABLE.............36
Table 1. Primer pairs...........36
FIGURES.............37
APPENDIX..............46
Appendix 1. Induction of Egr1 by different saturated and unsaturated FFAs.49
Appendix 2. ER stress induced by different ER stress inducer in shLuc and shEgr1 cells...........50
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