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標題: | 缺乏氧化壓力傳遞者NPGPx在小鼠與人類引起肥胖 Deficiency of NPGPx, an oxidative stress transducer, causes obesity in mice and human |
作者: | Yi-Cheng Chang 張以承 |
指導教授: | 李文華(Wen-Hwa Lee) |
共同指導教授: | 莊立民(Lee-Ming Chuang) |
關鍵字: | 氧化壓力,肥胖,脂肪細胞分化, oxidative stress,obesity,adipogenesis, |
出版年 : | 2013 |
學位: | 博士 |
摘要: | 流行病學顯示氧化壓力與肥胖緊密相關, 傳統上認為氧化壓力上升是肥胖所造成的結果, 但最近的證據顯示, 氧化壓力也會促進脂肪組織形成。NPGPx (non-selenocysteine-containing phospholipid hydroperoxide glutathione peroxidase or glutathione peroxidase 7, GPx7)是一個演化中保守的氧化壓力感受與傳遞者。我們之前的研究發現, 缺乏NPGPx會增加氧化壓力。在本研究中, 我們發現NPGPx在脂肪前趨細胞表現量豐富, 而減少其NPGPx的表現, 會促進脂肪前趨細胞分化為脂肪細胞。此促進脂肪分化的作用, 是藉由氧化壓力增加造成的CCAAT/enhancer-binding protein beta (C/EBPβ)的活化所達成, 抗氧化劑N-acetylcysteine可以壓制這些作用。我們也發現, 缺乏NPGPx的小鼠脂肪組織增加且脂肪細胞肥大,以N-acetylcysteine餵食NPGPx缺乏的小鼠, 可以防止這些表現型產生。我們進一步發現, 人類NPGPx基因的單一核苷酸多型性, 在數個人類族群中, 與身體質量指數有相關,也與人類脂肪組織中NPGPx訊息核醣核苷核酸的表現量有相關。總和來說, 本研究顯示NPGPx會經由調控氧化壓力, 影響脂肪細胞分化, 造成肥胖, 這結果揭示了氧化壓力在引發肥胖的角色, 以及抗氧化劑預防肥胖的可能療效。 Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. NPGPx (non-selenocysteine-containing phospholipid hydroperoxide glutathione peroxidase or glutathione peroxidase 7, GPx7) is an evolutionally conserved oxidative stress sensor/transducer. Deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this study, we showed that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx in preadipocytes facilitated its differentiation into adipocytes via ROS-dependent activation of CCAAT/enhancer-binding protein beta (C/EBPβ) pathway. This enhanced adipogenesis was suppressed by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index in several independent human populations. These results indicate that NPGPx modulates fat accumulation in mice and human via regulating ROS and highlight the importance of targeting redox homeostasis for treating obesity. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61906 |
全文授權: | 有償授權 |
顯示於系所單位: | 轉譯醫學博士學位學程 |
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