本文關(guān)鍵詞：Cidea以及Fsp27在脂肪代謝中的功能以及分子機(jī)制　出處：《清華大學(xué)》2010年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： Fsp27 Cidea Perilipin AMPK 脂滴

【摘要】：代謝綜合癥,特別是肥胖癥以及糖尿病已經(jīng)成為現(xiàn)代社會(huì)中嚴(yán)重危害人民健康的常見(jiàn)疾病。體內(nèi)能量代謝過(guò)程受到十分嚴(yán)格的調(diào)控。其中,脂肪組織在能量代謝平衡的調(diào)節(jié)中起到不可替代的重要地位。CIDE家族蛋白在能量代謝,特別是脂肪代謝的調(diào)控中具有重要且獨(dú)特的功能。三種基因(Cidea, Cideb以及Fsp27)敲除小鼠都表現(xiàn)明顯的瘦表型。其中,Fsp27基因敲除小鼠白色脂肪組織向棕色脂肪組織轉(zhuǎn)化,脂肪積累顯著降低,基礎(chǔ)脂水解加快,并且脂滴顯著變小。Cidea基因敲除小鼠棕色脂肪組織脂肪代謝速率顯著提高,脂肪酸氧化速率明顯加快。在本研究中,我們首先使用體外分離培養(yǎng)的胚胎成纖維細(xì)胞誘導(dǎo)分化得到的脂肪細(xì)胞為模型,在細(xì)胞水平上證實(shí)了Fsp27基因敲除對(duì)脂肪細(xì)胞脂代謝以及分化命運(yùn)的影響。然后以Fsp27為模型,研究分析了Fsp27誘導(dǎo)大脂滴形成的過(guò)程以及機(jī)制。發(fā)現(xiàn)Fsp27能夠通過(guò)在LDCS(脂滴連接位點(diǎn))上富集,誘導(dǎo)中性脂在LDCS相連接的脂滴之間發(fā)生快速的雙向擴(kuò)散作用,促進(jìn)中性脂由小脂滴向大脂滴的定向轉(zhuǎn)移作用,最終導(dǎo)致脂滴的融合以及一個(gè)更大的脂滴的形成。同時(shí),我們確定了Fsp27的CIDE-N結(jié)構(gòu)域能夠通過(guò)相互作用形成同源二聚體進(jìn)而調(diào)節(jié)Fsp27的功能。更進(jìn)一步的,我們發(fā)現(xiàn)Perilipin能夠特異地與Fsp27形成異源二聚體,并顯著提高Fsp27誘導(dǎo)大脂滴形成的能力。最后,我們通過(guò)各種細(xì)胞模型,證實(shí)了Cidea控制AMPK穩(wěn)定性進(jìn)而提高脂肪酸的β-氧化速率在棕色脂肪細(xì)胞中的生理作用。我們的研究結(jié)果揭示了CIDE家族蛋白Fsp27誘導(dǎo)脂滴融合長(zhǎng)大的一個(gè)全新機(jī)制。我們還證實(shí)并探索了Cidea以及Fsp27基因敲除對(duì)脂肪細(xì)胞代謝以及分化的影響及其分子機(jī)制。這些研究成果為確定CIDE家族蛋白在脂肪代謝中的重要作用以及代謝綜合癥的防治打下了堅(jiān)實(shí)的基礎(chǔ)。
[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.
【學(xué)位授予單位】：清華大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類(lèi)號(hào)】：R363

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本文編號(hào)：1363854