本文選題：非酒精性脂肪肝病 + MST1��； 參考：《北京協(xié)和醫(yī)學院》2016年碩士論文

【摘要】：隨著肥胖人口的日趨增長,非酒精性脂肪肝病(Non-alcoholic Fatty Liver Disease, NAFLD)的患者也日益增多。哺乳動物STE20激酶1(Mammalian Sterile 20-like Kinase 1, MST1)是一種絲氨酸/蘇氨酸激酶,同時也是Hippo信號通路中的一部分,參與細胞存活和凋亡等多種細胞生物過程。有研究表明MST1可以作為糖尿病治療新策略的靶點,它可以從其源頭對糖尿病進行抑制,即防止胰島p細胞的損傷。但MST1對肝臟脂肪代謝的影響依然不為人知。沉默交配型信息調節(jié)因子2同源蛋白1(Silent Mating Type Information Regulation 2 homolog I, SIRT1)是NAD+依賴的去乙�；�,是酵母沉默信息調控因子Sir2在哺乳動物中的同系物。它在細胞中含量豐富,參與眾多基因的轉錄調控、能量代謝及細胞衰老等地調節(jié)。但SIRT1與另一個重要的凋亡相關因子MST1之間的相互作用關系如何呢?本課題就這一問題進行了以下實驗。研究中發(fā)現(xiàn),在MST1敲除的小鼠肝臟中,由饑餓和高脂引發(fā)的肝臟代謝損傷比野生型129小鼠嚴重。研究中發(fā)現(xiàn)饑餓能夠明顯促進Mstl的mRNA水平。饑餓能促進SIRT1的表達,但是在Mst1的敲除鼠中,饑餓不能引發(fā)的SIRT1的過表達。肝原代細胞中,MST1的過表達能夠促進SIRT1的表達。這一結果在293A細胞中也得到了檢測并成立。MST1還可以抑制氧化應激產物的生成。隨后對MST1促進SIRT1表達的機制進行研究,發(fā)現(xiàn)MST1過表達時能夠抑制SIRT1的泛素化。這說明MST1對SIRT1的促進可能是通過抑制其泛素化來實現(xiàn)的。而且MST1過表達還能抑制Srebp-1c的表達,促進抗氧化基因的表達。因此得出如下結論,MST1參與調節(jié)的肝臟脂肪代謝是通過SIRT1基因影響調控的。這對非酒精性脂肪肝病的機制分析和治療有重大的前景和意義。
[Abstract]:With the increasing of obese population, the number of patients with non-alcoholic fatty liver disease (NAFLD) is increasing. Mammalian Sterile 20-like Kinase 1 (MST1) is a serine / threonine kinase, which is also a part of the Hippo signaling pathway and is involved in many cell biological processes, such as cell survival and apoptosis. Some studies have shown that MST1 can be used as a target of new strategies for the treatment of diabetes, and it can inhibit diabetes from its source, that is, to prevent the damage of islet p cells. However, the effect of MST1 on liver fat metabolism is still unknown. Silencing mating Type Information Regulation 2 homolog I (SIRT1) is NAD-dependent deacetylase and a homologue of yeast silencing information regulator Sir2 in mammals. It is abundant in cells and participates in the regulation of transcription, energy metabolism and cell senescence of many genes. But what is the interaction between SIRT1 and another important apoptosis-related factor MST1? The following experiments have been carried out on this subject. It was found that in MST1 knockout mice liver metabolic damage induced by starvation and high fat was more serious than that in wild 129 mice. It was found that hunger significantly promoted the mRNA level of Mstl. Hunger could promote the expression of SIRT1, but hunger could not induce the overexpression of SIRT1 in Mst1 knockout mice. Overexpression of MST1 in primary hepatocytes can promote the expression of SIRT1. This result was also detected in 293A cells. MST1 could also inhibit the production of oxidative stress products. The mechanism of MST1 promoting SIRT1 expression was studied. It was found that MST1 overexpression could inhibit the ubiquification of SIRT1. This suggests that the promotion of SIRT1 by MST1 may be achieved by inhibiting its ubiquification. The overexpression of MST1 also inhibited the expression of Srebp-1c and promoted the expression of antioxidant genes. It is concluded that MST1 participates in the regulation of hepatic fat metabolism through SIRT1 gene. It has great prospect and significance for mechanism analysis and treatment of non-alcoholic fatty liver disease.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R575

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