Early growth response-1 protects pancreatic beta-cells from free fatty acid-induced apoptosis
| Autor: | Mun-WaiCheong, 張文維 |
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| Rok vydání: | 2013 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 101 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. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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