载脂蛋白AI的抗肥胖作用研究及PAQR5在非小细胞肺癌中的功能研究
文献类型：学位论文
| 作者 | 阮祥博 |
| 学位类别 | 博士 |
| 答辩日期 | 2011-10-23 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 陈雁 |
| 关键词 | 肥胖 ApoA-I 非小细胞肺癌 PAQR5 |
| 其他题名 | Characterizing the role of Apolipoprotein A-I in obesity and the role of PAQR5 in non-small cell lung cancer |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 第一部分 载脂蛋白AI的抗肥胖作用研究 载脂蛋白AI（ApoA-I）是高密度脂蛋白（HDL）的主要蛋白组分。人群流行病学研究表明血浆中HDL和ApoA-I浓度的降低与肥胖及代谢综合征的发生密切相关，但ApoA-I是否能直接抵抗肥胖的发生未知。本研究利用两种小鼠模型——ApoA-I转基因小鼠和ApoA-I模拟肽D-4F处理小鼠研究了ApoA-I的抗肥胖作用。我们发现在小鼠体内高表达ApoA-I或者用D-4F处理均能明显减少高脂饲料诱导的白色脂肪堆积并改善胰岛素抵抗。代谢参数分析显示高表达ApoA-I或者用D-4F处理均能在小鼠体内增加能量支出。ApoA-I转基因小鼠褐色脂肪组织中解耦联蛋白1表达上调。ApoA-I和D-4F能在体外培养的褐色脂肪细胞中上调UCP1的表达并激活AMPK。我们的研究结果初步证实了ApoA-I具有直接的抗肥胖作用，并且这种作用是通过上调褐色脂肪组织中解耦联蛋白1（UCP1）从而增加能量支出来实现的。 第二部分 PAQR5在非小细胞肺癌中的功能研究 孕酮及脂联素受体（PAQR）家族是一类进化保守并含有七次跨膜结构的分子。该家族在哺乳动物中包含11个成员即PAQR1-PAQR11，其中PAQR5，PAQR7和PAQR8又被称为孕酮膜受体（mPRg, mPRa和 mPRb）。非小细胞肺癌（NSCLC）是人类健康的重大威胁，其高发病率、高致死率、高复发性以及低存活率使其成为肿瘤研究的焦点之一。一项mRNA芯片的数据显示PAQR5的表达水平在非小细胞肺癌的组织样品中显著降低，提示其可能在肺癌的发生发展中发挥作用。我们在NSCLC细胞系中过表达了PAQR5，检测其对肿瘤细胞增殖的影响。结果显示PAQR5可以抑制肿瘤细胞生长，阻碍细胞周期进程并降低其克隆形成能力，小鼠体内成瘤试验显示过表达PAQR5可以显著抑制肿瘤的生长。信号转导子和转录激活子3（Stat3）在包括NSCLC的多种肿瘤中均表现出组成性激活并促进肿瘤细胞增殖和存活。我们的研究显示过表达PAQR5可以显著抑Stat3的磷酸化，说明PAQR5很有可能是通过抑制Stat3的激活来阻碍肿瘤细胞增殖。我们的研究初步提示PAQR5有可能作为一个抑癌基因在肺癌的发生中发挥作用。 |
| 索取号 | D2011-144 |
| 英文摘要 | Part I Characterizing the role of Apolipoprotein A-I in obesity Apolipoprotein A-I (ApoA-I) is the most abundant protein constituent of high density lipoprotein (HDL). Reduced plasma HDL and ApoA-I levels have been found to be associated with obesity and metabolic syndrome in humans. However, whether or not ApoA-I has a direct effect on obesity is largely unknown. Here we analyzed the anti-obesity effect of ApoA-I using two mouse models, a transgenic mouse with overexpression of ApoA-I and the mice administered with an ApoA-I mimetic peptide D-4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA-I overexpression and D-4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA-I overexpression and D-4F treatment enhanced energy expenditure in the mice. Both the mRNA and protein levels of UCP1 in brown fat tissue were elevated by ApoA-I overexpression and D-4F treatment. ApoA-I and D-4F treatment could also increase UCP1 mRNA and protein levels in brown adipocytes in culture. Taken together, our results reveal that ApoA-I has an anti-obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue. Part II Characterizing the role of PAQR5 in non-small cell lung cancer PAQR (Progesterone and AdipoQ Receptor) family is conserved in evolution with typical seven-transmembrane strucuture. There are 11 family members in mamalians. Among the members of the PAQR family, PAQR5, PAQR7 and PAQR8 were fist identified as putative membrane progestin receptors in fish and named as mPRg, mPRa and mPRb. On the other hand, lung cancer is a major health challenge worldwide, ranking as one of the most common malignancies in the world. The most common form of lung cancers is non-small cell lung cancer (NSCLC), which comprises approximately 80% of all lung cancers. In a mRNA microarray assay we found that the expression of PAQR5 was significantly down-regulated in clinical NSCLC samples. Overexpression of PAQR5 in NSCLC cell lines suppressed cell growth, induced cell cycle arrest and inhibited colony formation in soft agar assay. In vivo study showed overexpression of PAQR5 inhibited tumorigenicity in xenografts. Further study revealed that overexpression of PAQR5 suppressed Signal Transducer and Activator of Transcription 3 (Stat3) activation which is constitutive activated in many cancers including NSCLC. Our results suggest PAQR5 may act as a tumor suppresser and play an important role in the development of lung cancer. |
| 语种 | 中文 |
| 源URL | [http://202.127.25.144/handle/331004/113]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_信号转导与营养相关疾病研究组 |
| 推荐引用方式 GB/T 7714 | 阮祥博. 载脂蛋白AI的抗肥胖作用研究及PAQR5在非小细胞肺癌中的功能研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2011. |
入库方式： OAI收割
来源：上海营养与健康研究所
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