Cidea以及Fsp27在脂肪代谢中的功能以及分子机制

发布时间：2018-01-01 09:12

本文关键词：Cidea以及Fsp27在脂肪代谢中的功能以及分子机制　出处：《清华大学》2010年博士论文　论文类型：学位论文

更多相关文章： Fsp27 Cidea Perilipin AMPK 脂滴

【摘要】：代谢综合症,特别是肥胖症以及糖尿病已经成为现代社会中严重危害人民健康的常见疾病。体内能量代谢过程受到十分严格的调控。其中,脂肪组织在能量代谢平衡的调节中起到不可替代的重要地位。CIDE家族蛋白在能量代谢,特别是脂肪代谢的调控中具有重要且独特的功能。三种基因(Cidea, Cideb以及Fsp27)敲除小鼠都表现明显的瘦表型。其中,Fsp27基因敲除小鼠白色脂肪组织向棕色脂肪组织转化,脂肪积累显著降低,基础脂水解加快,并且脂滴显著变小。Cidea基因敲除小鼠棕色脂肪组织脂肪代谢速率显著提高,脂肪酸氧化速率明显加快。在本研究中,我们首先使用体外分离培养的胚胎成纤维细胞诱导分化得到的脂肪细胞为模型,在细胞水平上证实了Fsp27基因敲除对脂肪细胞脂代谢以及分化命运的影响。然后以Fsp27为模型,研究分析了Fsp27诱导大脂滴形成的过程以及机制。发现Fsp27能够通过在LDCS(脂滴连接位点)上富集,诱导中性脂在LDCS相连接的脂滴之间发生快速的双向扩散作用,促进中性脂由小脂滴向大脂滴的定向转移作用,最终导致脂滴的融合以及一个更大的脂滴的形成。同时,我们确定了Fsp27的CIDE-N结构域能够通过相互作用形成同源二聚体进而调节Fsp27的功能。更进一步的,我们发现Perilipin能够特异地与Fsp27形成异源二聚体,并显著提高Fsp27诱导大脂滴形成的能力。最后,我们通过各种细胞模型,证实了Cidea控制AMPK稳定性进而提高脂肪酸的β-氧化速率在棕色脂肪细胞中的生理作用。我们的研究结果揭示了CIDE家族蛋白Fsp27诱导脂滴融合长大的一个全新机制。我们还证实并探索了Cidea以及Fsp27基因敲除对脂肪细胞代谢以及分化的影响及其分子机制。这些研究成果为确定CIDE家族蛋白在脂肪代谢中的重要作用以及代谢综合症的防治打下了坚实的基础。
[Abstract]:Metabolic syndrome, especially obesity and diabetes, has become a common disease in modern society that seriously endangers people's health. The process of energy metabolism in the body is strictly regulated. Adipose tissue plays an irreplaceable role in the regulation of energy metabolism balance. CIDE family proteins play an important role in energy metabolism. In particular, the regulation of fat metabolism has an important and unique function. Three genes, Cidea, Cideb and Fsp27) knockout mice all showed obvious thin phenotype. In Fsp27 knockout mice, white adipose tissue transformed into brown adipose tissue, fat accumulation decreased significantly and basic lipid hydrolysis accelerated. The fat metabolism rate and fatty acid oxidation rate of brown adipose tissue in Cidea knockout mice were significantly increased. We first used adipocytes derived from embryonic fibroblasts isolated and cultured in vitro as models. The effects of Fsp27 knockout on lipid metabolism and differentiation fate of adipocytes were confirmed at cellular level. Then Fsp27 was used as a model. The process and mechanism of Fsp27 induced lipid droplet formation were analyzed. It was found that Fsp27 can be enriched on LDCS (lipid drop junction site). It induced the fast bidirectional diffusion of neutral lipid between the lipid droplets connected with LDCS, and promoted the directional transfer of neutral lipid from small lipid droplets to large lipid droplets. Ultimately leads to the fusion of lipid droplets and the formation of a larger lipid droplet. At the same time. We have determined that the CIDE-N domain of Fsp27 can interact to form homologous dimers and then regulate the function of Fsp27. We found that Perilipin can specifically form heterodimers with Fsp27 and significantly improve the ability of Fsp27 to induce the formation of large lipid droplets. Finally, we use various cell models. It is confirmed that Cidea controls the stability of AMPK and enhances the 尾 -oxidation rate of fatty acids in brown adipocytes. Our results reveal the induction of Fsp27 by CIDE family proteins. We have also confirmed and explored the effects of Cidea and Fsp27 knockout on adipocyte metabolism and differentiation and their molecular mechanisms. The important role of IDE family proteins in fat metabolism and the prevention and treatment of metabolic syndrome lay a solid foundation.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R363

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