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標題: | 剔除N端乙醯基轉移酶有助於強化能量代謝並保護小鼠免於飲食引起之肥胖症 Naa10p knockout protects mice form diet-induced obesity through enhanced energy consumption |
作者: | Yi-Chun Shih 施議鈞 |
指導教授: | 阮麗蓉(Jung-Juan Li) |
關鍵字: | 乙醯基轉移?,肥胖,代謝,脂肪分化,棕色脂肪,棕化, Naa10,N-α-acetyltransferase 10,diet-induced obesity,adipogenesis,Pparγ,3T3-L1,browning, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | Naa10p (N-α-acetyltransferase 10 protein) 作為主要的乙醯基轉移酶,可於超過50%的哺乳類蛋白質加上乙醯基。此外,Naa10p也是個具有DNA結合能力的蛋白質,能夠促進甲基轉移酶DNA methyltransferase 1 (DNMT1)與DNA結合,調控基因甲基化。已知Naa10p在癌症形成扮演重要角色,Naa10p突變則造成嚴重發育遲緩及與X染色體關聯人類疾病。我們實驗室研究更指出,Naa10p剔除小鼠較正常小鼠瘦小,平均體重減少百分之二十。本篇論文,主要研究Naa10p在脂肪生成與代謝上所扮演的角色。本篇研究發現,長期餵食高脂飼料的Naa10基因剔除鼠比正常小鼠能抵抗飲食引起的肥胖與胰島素抗性。長期餵食高脂飼料的Naa10基因剔除鼠的皮下脂肪較少,並伴隨著較強的生理代謝率以及脂肪棕化現象。此外,缺少Naa10p的白脂肪前驅細胞3T3-L1在脂肪生成的能力上有所缺損。這個現象可以透過重新表現正常Naa10p或是給與過氧化體增生活化接受器(Pparγ)之促進劑troglitazone而恢復。透過表現不同Naa10p突變蛋白,我們也證實此現象主要是受到Naa10p乙醯基轉移酶活性的調控。除此之外,我們也提出Naa10p能夠直接與Pparγ交互作用的證據。Pparγ在脂肪生成中扮演著核心的調控角色,同時也在白色脂肪組織中生成似棕色脂肪細胞的過程中扮演決定性的角色,且此現象受到Pparγ上離胺酸乙醯化的調控。因此,Naa10p或許是透過改變Pparγ的乙醯化來抑制脂肪細胞的棕化現象並促進前驅細胞分化為白色脂肪的品系。根據我們的研究,我們提出Naa10p在脂肪生成與代謝上所扮演的新角色,並提出一個具有潛力針對飲食引起的肥胖的治療策略。 Naa10p (N-α-acetyltransferase 10 protein) is the major N-α-acetyltransferase that acetylates more than 50% of proteins in mammalian cells. Naa10p is also a DNA binding protein which mediates gene-specific DNA methylation by recruiting DNMT1 (DNA methyltransferase 1). Studies have indicated that Naa10p plays an important role in cancer formation and Naa10p mutation causes severe developmental delay in human. Our laboratory also found that Naa10p knockout mice showed 20% reduction in body weight and size. This thesis aims to understand the role of Naa10p in adipogenesis and metabolism. We found that Naa10 knockout (Naa10-KO) mice were protected from high fat diet (HFD)-induced obesity and insulin resistance. HFD-fed Naa10-KO mice had less subcutaneous fat which is also accompanied with increased energy expenditure and browning of preadipocyte. In addition, white preadipocyte 3T3-L1 with Naa10p depletion led to impaired adipogenesis which could be rescued by adding back WT Naa10p or treating with Pparγ agonist troglitazone. We also demonstrated that this phenotype is acetyltransferase activity-dependent as adding back enzyme-dead Naa10 mutant protein could not rescue the phenotype. Furthermore, we provided evidence that Naa10p directly interacts with Pparγ. Pparγ plays a central role in adipogenesis and determination of white-to-brown plasticity in white adipose tissue which is regulated by lysine acetylation. Thus, Naa10p might inhibit browning and promote white lineage differentiation through mediating acetylation of Pparγ. These results reveal a novel role of Naa10p in adipogenesis and metabolism which provide a potential new therapeutic strategy against diet-induce obesity. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49791 |
DOI: | 10.6342/NTU201602434 |
全文授權: | 有償授權 |
顯示於系所單位: | 分子醫學研究所 |
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