MST1通过抑制SIRT1的泛素化调节肝脏的脂肪代谢

发布时间：2018-06-28 12:32

本文选题：非酒精性脂肪肝病 + MST1　；参考：《北京协和医学院》2016年硕士论文

【摘要】：随着肥胖人口的日趋增长,非酒精性脂肪肝病(Non-alcoholic Fatty Liver Disease, NAFLD)的患者也日益增多。哺乳动物STE20激酶1(Mammalian Sterile 20-like Kinase 1, MST1)是一种丝氨酸/苏氨酸激酶,同时也是Hippo信号通路中的一部分,参与细胞存活和凋亡等多种细胞生物过程。有研究表明MST1可以作为糖尿病治疗新策略的靶点,它可以从其源头对糖尿病进行抑制,即防止胰岛p细胞的损伤。但MST1对肝脏脂肪代谢的影响依然不为人知。沉默交配型信息调节因子2同源蛋白1(Silent Mating Type Information Regulation 2 homolog I, SIRT1)是NAD+依赖的去乙酰化酶,是酵母沉默信息调控因子Sir2在哺乳动物中的同系物。它在细胞中含量丰富,参与众多基因的转录调控、能量代谢及细胞衰老等地调节。但SIRT1与另一个重要的凋亡相关因子MST1之间的相互作用关系如何呢?本课题就这一问题进行了以下实验。研究中发现,在MST1敲除的小鼠肝脏中,由饥饿和高脂引发的肝脏代谢损伤比野生型129小鼠严重。研究中发现饥饿能够明显促进Mstl的mRNA水平。饥饿能促进SIRT1的表达,但是在Mst1的敲除鼠中,饥饿不能引发的SIRT1的过表达。肝原代细胞中,MST1的过表达能够促进SIRT1的表达。这一结果在293A细胞中也得到了检测并成立。MST1还可以抑制氧化应激产物的生成。随后对MST1促进SIRT1表达的机制进行研究,发现MST1过表达时能够抑制SIRT1的泛素化。这说明MST1对SIRT1的促进可能是通过抑制其泛素化来实现的。而且MST1过表达还能抑制Srebp-1c的表达,促进抗氧化基因的表达。因此得出如下结论,MST1参与调节的肝脏脂肪代谢是通过SIRT1基因影响调控的。这对非酒精性脂肪肝病的机制分析和治疗有重大的前景和意义。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R575

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