2型糖尿病线粒体损伤和修复机制
文献类型:学位论文
作者 | 郝杰杰 |
学位类别 | 博士 |
答辩日期 | 2009 |
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 | 线粒体生成 过氧化物激活酶转录因子-γ激活因子-1a RNA干扰 腺病毒 |
其他题名 | Mechanisms of mitochondrial dysfunction and reduction |
学位专业 | 生物化学与分子生物学 |
中文摘要 | 第一部分:为了进一步明确线粒体生成在2型糖尿病及胰岛素抵抗中的作用,尝试应用有效的营养素干预来预防糖尿病的发生,我们具体研究了HT在3T3-L1脂肪细胞线粒体生成中的作用。发现HT显著的增加线粒体的生成和线粒体的功能。这些变化伴随着PGC-1a及其下游转录因子表达的的升高。 并且HT能够激活AMP激酶, 抑制乙酰辅酶A羧化酶ACC的活性。 通过腺病毒RNA干扰方法,我们进一步研究了HT发挥作用所依赖的信号通路。在骨骼肌细胞C2C12胰岛素抵抗的模型中,HT也能够明显增加胰岛素敏感性。研究结果表明HT可有效治疗和预防糖尿病。 另外,我们也研究了HT对于巢癌卵细胞OVCAR-3生长抑制及其促进肿瘤细胞凋亡的分子机制,提示HT也具有抑制肿瘤生长的功能。 第二部分:为了研究线粒体功能紊乱、氧化应激在2型糖尿病及其免疫功能低下的发生发展过程中的作用,并且尝试多种复合物治疗糖尿病的机制及其可行性,同时反证线粒体功能障碍、氧化损伤与2型糖尿病和免疫紊乱发生、发展的密切联系, 我们运用2型糖尿病GK大鼠模型,研究了四种线粒体营养素组合物改善2型糖尿病及其免疫功能的作用机制。结果表明,GK大鼠模型组的胸腺和脾脏的免疫功能显著降低,免疫调节的细胞因子失调, 免疫细胞亚型CD4+/CD8+比值改变;而且氧化损伤指标增加, 抗氧化能力线粒体膜电位降低等, 同时促凋亡的蛋白表达显著升高。药物干预后,包括低剂量组合物以及阳性对照pioglitazone的处理组能够明显或者 部分逆转这些现象。而且组合物具有优于pioglitazone的效果。 我们进一步研究,发现药物干预能够显著促进组合物组GK大鼠骨骼比目鱼肌的线粒体生成,增强骨骼肌的线粒体功能。对其肝脏组织的检测也表明营养素组合物能够显著改善肝脏中脂肪代谢和线粒体功能的紊乱,保护肝脏免受氧化损伤,并抑制肝脏细胞的凋亡 。 |
索取号 | D2009-132 |
英文摘要 | Part I: Hydroxytyrosol (HT) in extra-virgin olive oil is considered one of the most important polyphenolic compounds responsible for the health benefits of the Mediterranean diet for lowering incidence of cardiovascular disease. In the present study, we investigated the effects of HT to stimulate mitochondrial biogenesis and promote mitochondrial function in 3T3-L1 adipocytes. HT stimulated the promoter transcriptional activation and protein expression of PPARGC1a and its downstream targets, which leads to an increase of mtDNA and number of mitochondria. Knock-down of Ppargcla by siRNA blocked HT’s stimulating effect on complex I expression and mtDNA copy number. The HT treatment resulted in an enhancement of insulin sensitivity and mitochondrial function. In differentiated C2C12 skeletal muscle cells, HT could increase the insulin sensitivity and stimulate mitochondrial biogenesis (unpublished). In addition, we investigated the effects of HT on the proliferation and apoptosis of human ovarian cancer cell line OVCAR-3. Part II: In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial targeting nutrients. We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function, and inhibited the elevation of apoptosis factors. We further demonstrated that defects of glucose and lipid metabolism are associated with low mitochondrial biogenesis and function in skeletal muscle of the diabetic Goto-Kakizaki rats. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. In addition, we investigated their effects of the combination of the four mitochondria-targeting nutrients, compared with pioglitazone, on mitochondrial function, oxidative stress and apoptosis in the liver of GK rats. These results suggest that dietary supplementation of mitochondrial targeting nutrients may be an effective strategy to improve symptoms of diabetes in GK rats by improving mitochondrial and immune function, inhibiting oxidative stress and reducing apoptosis. |
语种 | 中文 |
公开日期 | 2015-09-01 |
源URL | [http://202.127.25.144/handle/331004/124] ![]() |
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 | 郝杰杰. 2型糖尿病线粒体损伤和修复机制[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. 2009. |
入库方式: OAI收割
来源:上海营养与健康研究所
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