本文選題：CIDEC + 肥胖��； 參考：《第四軍醫(yī)大學(xué)》2010年博士論文

【摘要】：隨著社會(huì)經(jīng)濟(jì)的發(fā)展,人們的生活方式的轉(zhuǎn)變,肥胖(obesity)已成為當(dāng)前世界性的健康問(wèn)題,是誘發(fā)糖尿病、心腦血管疾病等多種代謝相關(guān)疾病的重要危險(xiǎn)因素,其與吸煙、艾滋病并稱為人類健康的三大殺手。研究發(fā)現(xiàn),脂肪細(xì)胞的分化與肥胖的發(fā)生有著密切的關(guān)系。因此,研究脂肪細(xì)胞的分化及其機(jī)制,對(duì)于預(yù)防肥胖的發(fā)生,治療肥胖及相關(guān)疾病具有重要意義。 CIDE(cell death-inducing DFF45-like effectors)家族是20世紀(jì)末發(fā)現(xiàn)的一組能夠誘導(dǎo)細(xì)胞凋亡的新基因。CIDE家族主要包括CIDEA、CIDEB和CIDEC(在小鼠稱為FSP27)。最近研究發(fā)現(xiàn)CIDE家族成員與肥胖的發(fā)生密切相關(guān)。CIDEA、CIDEB和FSP27敲除小鼠,均能抵制高脂飲食誘導(dǎo)的肥胖。其中FSP27是小鼠脂肪特異性蛋白,僅在成熟的脂肪細(xì)胞中表達(dá),與脂肪細(xì)胞分化密切相關(guān),并且具有抑制脂肪分解促進(jìn)脂肪儲(chǔ)積的作用。CIDEC,作為FSP27的人類同源物,其在人體內(nèi)功能及機(jī)制尚不明確。因此本課題將著重研究CIDEC在人類脂肪細(xì)胞分化中的作用,期望為今后治療肥胖提供新的靶點(diǎn)。 【目的】 1、研究CIDEC的表達(dá)與脂肪細(xì)胞分化的關(guān)系;2、研究CIDEC的亞細(xì)胞定位;3、研究下調(diào)CIDEC表達(dá)對(duì)脂肪細(xì)胞分化的影響及機(jī)制。 【方法】 1、利用免疫組織化學(xué)、Real-time PCR和Western blot方法檢測(cè)CIDEC在不同發(fā)育階段的人胚胎脂肪組織以及不同分化程度脂肪腫瘤組織中的表達(dá)變化;2、構(gòu)建CIDEC與熒光蛋白融合表達(dá)的質(zhì)粒,利用脂質(zhì)體轉(zhuǎn)染COS-7細(xì)胞,以確定CIDEC蛋白的亞細(xì)胞定位。3、體外原代培養(yǎng)人前脂肪細(xì)胞,并進(jìn)行誘導(dǎo)分化,檢測(cè)不同分化階段CIDEC的表達(dá)水平。4、利用慢病毒siRNA沉默CIDEC的表達(dá),以研究下調(diào)CIDEC表達(dá)對(duì)脂肪細(xì)胞分化的影響,并分析其機(jī)制。 【結(jié)果】 1、CIDEC的表達(dá)水平與脂肪細(xì)胞的分化相關(guān) 我們采用免疫組織化學(xué)、Real-time PCR和Western blot方法比較了3例不同發(fā)育階段的胎兒脂肪組織中CIDEC的表達(dá)情況,同時(shí)檢測(cè)調(diào)控脂肪細(xì)胞分化關(guān)鍵分子PPARγ的變化。結(jié)果顯示,無(wú)論mRNA還是蛋白水平,CIDEC均呈現(xiàn)隨著分化成熟逐漸增高的趨勢(shì),并且與PPARγ的表達(dá)趨勢(shì)完全一致。對(duì)30例人體正常脂肪組織和45例不同分化程度的脂肪腫瘤組織的免疫組織化學(xué)染色結(jié)果顯示,CIDEC隨著脂肪細(xì)胞分化程度降低而表達(dá)降低。采用Real-time PCR和Western blot方法的研究結(jié)果顯示,同正常脂肪組織相比,脂肪瘤中CIDEC的表達(dá)變化不顯著,而分化好的脂肪肉瘤、黏液型脂肪肉瘤及去分化脂肪肉瘤中CIDEC的表達(dá)均顯著降低(n=5, *p0.05)。此外,通過(guò)體外實(shí)驗(yàn)原代培養(yǎng)人前脂肪細(xì)胞,并誘導(dǎo)成為成熟脂肪細(xì)胞,隨著脂肪細(xì)胞的誘導(dǎo)分化成熟,CIDEC和PPARγ的表達(dá)水平同誘導(dǎo)前相比急劇升高(*p0.05),同脂肪分化標(biāo)志分子FABP4變化趨勢(shì)一致。以上體內(nèi)、外實(shí)驗(yàn)結(jié)果提示,CIDEC在脂肪細(xì)胞分化過(guò)程中發(fā)揮重要作用。 2、CIDEC蛋白主要定位于脂滴表面,與線粒體沒(méi)有共定位 我們采用脂質(zhì)體轉(zhuǎn)染法將重組質(zhì)粒pShuttle-CMV-EGFP-CIDEC和pShuttle-CMV-DsRed1-CIDEC轉(zhuǎn)染COS-7細(xì)胞。以GFP-adipophilin作為脂滴的標(biāo)志物;Bodipy 493/503作為中性脂肪染料;MitoTracker Red CMXRos作為線粒體染料;Hoechst 33258作為細(xì)胞核染料。結(jié)果顯示:CIDEC分布于脂滴周圍,與adipophilin共定位,說(shuō)明CIDEC是一個(gè)定位于脂滴表面的蛋白;同時(shí)我們發(fā)現(xiàn)CIDEC與線粒體不存在共定位。 3、下調(diào)CIDEC的表達(dá)水平,脂肪細(xì)胞的分化受到抑制 我們首先構(gòu)建了攜帶針對(duì)CIDEC的高效siRNA的慢病毒,將原代培養(yǎng)的人前脂肪細(xì)胞在誘導(dǎo)分化以前感染此慢病毒,觀察下調(diào)CIDEC的表達(dá)對(duì)脂肪細(xì)胞分化的影響。結(jié)果發(fā)現(xiàn),下調(diào)CIDEC表達(dá)水平后,脂肪細(xì)胞內(nèi)脂滴體積明顯減小,脂肪含量也顯著降低,失去了成熟脂肪細(xì)胞的表型。進(jìn)一步研究發(fā)現(xiàn),CIDEC低表達(dá)后,細(xì)胞內(nèi)甘油三酯含量降低,而培養(yǎng)液中甘油的含量卻顯著增高。分子水平研究發(fā)現(xiàn),成熟脂滴標(biāo)志分子perilipin以及脂肪細(xì)胞分化標(biāo)志分子FABP4表達(dá)水平顯著降低。以上實(shí)驗(yàn)說(shuō)明,下調(diào)CIDEC的表達(dá)使甘油三酯合成降低,分解增強(qiáng),此外脂滴的成熟也受到影響,從而抑制了脂肪細(xì)胞的分化。 【結(jié)論】 本研究發(fā)現(xiàn)CIDEC是一個(gè)脂滴表面蛋白,CIDEC的表達(dá)與脂肪細(xì)胞分化相關(guān),CIDEC可能通過(guò)抑制脂肪的分解,促進(jìn)脂滴的成熟,從而參與了脂肪細(xì)胞的分化過(guò)程。如果抑制了CIDEC的表達(dá),可阻止脂肪細(xì)胞的分化,防止肥胖的發(fā)生,因此CIDEC有望成為治療肥胖的新靶點(diǎn)。
[Abstract]:With the development of social economy, the transformation of people's life style, obesity (obesity) has become the current world health problem, is an important risk factor to induce diabetes, cardiovascular and cerebrovascular diseases and other metabolic related diseases, which are the three major killers of smoking, AIDS and human health. Research found that the differentiation and fertilizer of fat cells There is a close relationship between the occurrence of fat and the study of the differentiation and mechanism of adipocyte, which is of great significance in preventing the occurrence of obesity and in the treatment of obesity and related diseases.
The CIDE (cell death-inducing DFF45-like effectors) family was found in the late twentieth Century a group of new genes that can induce apoptosis, including CIDEA, CIDEB, and CIDEC (in mice called FSP27). Recent studies have found that CIDE family members are closely related to the occurrence of obesity. Diet induced obesity, in which FSP27 is a fat specific protein in mice, is expressed only in mature adipocytes, closely related to the differentiation of fat cells, and has the effect of inhibiting fat decomposition and promoting the accumulation of fat,.CIDEC. As a human homologue of FSP27, its function and mechanism in human body is not clear. Therefore, this topic will focus on the research. The role of CIDEC in human adipocyte differentiation is expected to provide a new target for future treatment of obesity.
[Objective]
1, we studied the relationship between the expression of CIDEC and adipocyte differentiation; 2, we studied the subcellular localization of CIDEC; 3, we studied the effect of down-regulation of CIDEC expression on adipocyte differentiation and its mechanism.
[method]
1, immunohistochemistry, Real-time PCR and Western blot were used to detect the changes in the expression of CIDEC in human fetal adipose tissue and different degree of differentiation of fat tumor tissues at different developmental stages. 2, the plasmids fused with CIDEC and fluorescent protein were constructed, and COS-7 cells were transfected by liposomes to determine the subcellular localization of CIDEC protein. .3, the primary human preadipocytes were cultured in vitro, and the differentiation was induced, the expression level of CIDEC in different stages of differentiation.4 was detected. The expression of CIDEC was silenced by lentivirus siRNA, in order to study the effect of down regulation of CIDEC expression on the differentiation of adipocytes and to analyze the mechanism.
[results]
1, the expression level of CIDEC is related to adipocyte differentiation.
We used immunohistochemistry, Real-time PCR and Western blot to compare the expression of CIDEC in 3 fetal adipose tissues at different developmental stages, and also detected the changes in the key molecule PPAR gamma regulating the differentiation of adipocyte differentiation. The results showed that CIDEC showed a gradual increase in the level of differentiation and maturity regardless of mRNA or protein levels. The trend of the expression was consistent with the expression trend of PPAR gamma. Immunohistochemical staining of 30 normal fat tissues and 45 adipose tumor tissues with different degrees of differentiation showed that the expression of CIDEC decreased with the decrease in the degree of adipocyte differentiation. The results of the Real-time PCR and Western blot methods showed that the same normal fat was the same as normal fat. The expression of CIDEC in lipoma was not significant in lipoma, but the expression of CIDEC in well differentiated liposarcoma, mucous liposarcoma and dedifferentiated liposarcoma was significantly decreased (n=5, *p0.05). In addition, human preadipocytes were cultured in vitro and induced to become mature adipocytes, with the induction of adipocytes. The expression level of CIDEC and PPAR gamma increased sharply compared with that before induction (*p0.05), which was the same as that of the fat differentiation marker FABP4. In vivo, the experimental results suggest that CIDEC plays an important role in the process of adipocyte differentiation.
2, CIDEC protein is mainly located on the surface of lipid droplets and is not Co located with mitochondria.
We used the liposome transfection to transfect the recombinant plasmid pShuttle-CMV-EGFP-CIDEC and pShuttle-CMV-DsRed1-CIDEC into COS-7 cells. GFP-adipophilin was used as a marker for lipid droplets; Bodipy 493/503 was used as a neutral fatty dye; MitoTracker Red CMXRos was used as a mitochondrial dye; Hoechst 33258 was used as a nuclear dye. The results showed: CIDEC distribution The location of adipophilin around the lipid droplet indicates that CIDEC is a protein located on the surface of lipid droplets. At the same time, we found that there is no co localization between CIDEC and mitochondria.
3, down regulate the expression level of CIDEC and inhibit the differentiation of adipocytes.
We first constructed a slow virus carrying high efficiency siRNA for CIDEC. The primary cultured preadipocytes infected the lentivirus before inducing differentiation and observed the effect of down regulation of the expression of CIDEC on the differentiation of adipocytes. The results showed that the fat droplet volume decreased obviously and the fat content was significant after the downregulation of CIDEC expression level. Further studies found that the content of triglycerides in the cells decreased and the content of glycerol in the culture medium increased significantly after the low expression of CIDEC. Molecular level studies found that the expression level of the mature lipid droplet marker molecule perilipin and the biomarker of adipocyte differentiation was significantly reduced. The above results showed that the level of FABP4 expression was significantly reduced. The results showed that the expression of CIDEC decreased, the triglyceride synthesis decreased, the decomposition increased, and the maturation of lipid droplets was also affected, thus inhibiting the differentiation of adipocytes.
[Conclusion]
This study found that CIDEC is a lipid droplet surface protein, and the expression of CIDEC is related to the differentiation of fat cells. CIDEC may inhibit the decomposition of fat and promote the maturation of lipid droplets, thus participating in the differentiation process of fat cells. If the expression of CIDEC is suppressed, the differentiation of adipocytes can be prevented and obesity is prevented, so CIDEC is expected to become a promising one. It is a new target for the treatment of obesity.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R363

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8 小薇;臺(tái)灣開(kāi)發(fā)出人類脂肪基因芯片[N];醫(yī)藥經(jīng)濟(jì)報(bào);2002年

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4 周一然;蛋白激酶C-βΙ和-δ在脂肪細(xì)胞分化中的作用[D];中國(guó)科學(xué)院研究生院（上海生命科學(xué)研究院）;2006年

5 陳月;蛋白酪氨酸磷酸酶1B在3T3-L1前脂肪細(xì)胞分化中的作用研究[D];第二軍醫(yī)大學(xué);2007年

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