本文選題：非酒精性脂肪性肝病 + 內(nèi)質(zhì)網(wǎng)應激��； 參考：《浙江大學》2014年碩士論文

【摘要】：目的：非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是近年來影響人民生活健康的常見肝病之一。研究發(fā)現(xiàn),內(nèi)質(zhì)網(wǎng)應激(endoplasmic reticulum stress, ERS)在NAFLD發(fā)生發(fā)展過程中發(fā)揮重要作用,其確切分子機制尚未明確。本課題旨在分析內(nèi)質(zhì)網(wǎng)分子伴侶蛋白質(zhì)二硫鍵異構(gòu)酶A3前體(protein disulfide isomerase A3precursor, PDIA3/ERp57)在NAFLD中的作用及分子機制。 方法：本研究運用軟脂酸(palmitic acid, PA)誘導人正常肝細胞系L02細胞建立NAFLD細胞模型。在此基礎上,采用小分子RNA干擾(siRNA)、免疫印記、細胞凋亡檢測等分子生物學手段,系統(tǒng)研究內(nèi)質(zhì)網(wǎng)分子伴侶PDIA3在NAFLD發(fā)生發(fā)展過程中的作用及分子機制。 結(jié)果：(1)用PA成功建立NAFLD細胞模型；(2)PDIA3在NAFLD細胞模型中表達上調(diào)；(3)NAFLD細胞模型中,siRNA抑制PDIA3表達后引起細胞脂變加重、凋亡增多；(4)NAFLD細胞模型中,siRNA抑制PDIA3表達后引起脂肪酸合成酶(fatty acid synthase, FAS)、磷酸化的PKR樣內(nèi)質(zhì)網(wǎng)調(diào)節(jié)激酶(phospho-PKR-like ER kinase, P-PERK)、葡萄糖調(diào)節(jié)蛋白78(glucose-regulatedprotein78, GRP78)和C/EBP同源蛋白(C/EBP homologous protein, CHOP)表達升高。 結(jié)論：(1)PDIA3參與NAFLD的發(fā)生發(fā)展；(2)PDIA3表達抑制通過上調(diào)FAS蛋白表達加重軟脂酸誘導的肝細胞脂肪變性；(3)PDIA3表達抑制通過激活PERK-CHOP通路加重軟脂酸誘導的肝細胞ERS及其相關凋亡。本課題的順利實施為深入認識NAFLD的分子機制,發(fā)現(xiàn)新的診斷和治療靶標提供了理論依據(jù)。
[Abstract]:Objective: nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases affecting people's health in recent years. It is found that endoplasmic reticulum stress (ERSs) plays an important role in the development of NAFLD, and its exact molecular mechanism is not clear. The purpose of this study was to analyze the role and molecular mechanism of endoplasmic reticulum molecular chaperone protein disulfide isomerase A3 precursor. PDIA 3 / ERp57 in NAFLD. Methods: NAFLD cell model was induced by palmitic acidin (PAA) in human normal liver cell line L02. On this basis, the role and molecular mechanism of endoplasmic reticulum molecular chaperone PDIA3 in the pathogenesis and development of NAFLD were systematically studied by means of molecular biological methods such as small molecular RNA interference siRNAs, immunological imprinting and cell apoptosis detection. Results (1) NAFLD cell model was successfully established with PA. In NAFLD cell model, the expression of NAFLD was upregulated and increased after inhibiting the expression of PDIA3. The inhibition of PDIA3 expression by siRNA in NAFLD cell model resulted in the increased expression of fatty acid synthase (FASA), phospho-PKR-like kinase (P-PERKN), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein C / EBP homologous protein, CHOP). Conclusion the inhibition of PDIA3 expression in NAFLD by up-regulating the expression of FAS protein increases the inhibition of PDIA3 expression in hepatocytes induced by palmitic acid. The inhibition of PDIA3 expression by activating the PERK-CHOP pathway can aggravate the ERS and its related apoptosis in hepatocytes induced by palmitic acid. The successful implementation of this project provides a theoretical basis for further understanding the molecular mechanism of NAFLD and finding new diagnostic and therapeutic targets.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R575

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相關期刊論文 前1條

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本文編號：1820818