本文選題：SIRT6　切入點(diǎn)：脂肪組織　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

【摘要】：肥胖是誘發(fā)Ⅱ型糖尿病、動(dòng)脈粥樣硬化和腫瘤的危險(xiǎn)因素。雖然肥胖的發(fā)病率在30年間翻了一倍,但是目前的醫(yī)療界仍然缺乏有效的手段治療肥胖�？紤]到棕色和米色脂肪能夠解偶聯(lián)氧化磷酸化,將化學(xué)能轉(zhuǎn)化成熱能,增加機(jī)體的能量消耗,它們成為了人類戰(zhàn)勝肥胖的新希望。SIRT6與Sirtuins家族的其他成員不同,它位于細(xì)胞核內(nèi)的染色質(zhì)上,是具有ADP-核糖基轉(zhuǎn)移酶和依賴于NAD+的去乙�；富钚缘牡鞍酌�。研究表明,SIRT6在調(diào)控基因組穩(wěn)定性、衰老、糖代謝、應(yīng)激反應(yīng)、壽命、晝夜節(jié)律、心肌肥大和腫瘤的發(fā)生及發(fā)展中扮演重要角色,但是SIRT6在脂肪組織中的功能還有待發(fā)掘。我們的研究表明,SIRT6在棕色脂肪組織中的表達(dá)量明顯高于其在白色脂肪組織的表達(dá)水平,并且肥胖小鼠棕色脂肪組織中SIRT6的表達(dá)量顯著降低。冷刺激和β-激動(dòng)劑能夠促進(jìn)SIRT6在棕色和白色皮下脂肪組織中的表達(dá)。脂肪組織特異性敲除Sirt6會(huì)削弱小鼠棕色脂肪的產(chǎn)熱功能,使小鼠的棕色脂肪發(fā)生明顯的“白色化”,同時(shí)小鼠的氧氣消耗速率降低、體溫下降,并導(dǎo)致敲除小鼠的肥胖。此外,敲除小鼠還有高血脂癥、胰島素抵抗和脂肪肝等異常的代謝表型。脂肪組織特異性敲除Sirt6使得小鼠的能量消耗減少,脂肪酸氧化和產(chǎn)熱受到抑制。我們還發(fā)現(xiàn)敲除Sirt6致使小鼠缺乏對冷刺激和β3腎上腺素受體激動(dòng)劑CL316,243介導(dǎo)的產(chǎn)熱產(chǎn)生響應(yīng)。在原代小鼠棕色脂肪細(xì)胞中敲除Sirt6,會(huì)顯著抑制產(chǎn)熱相關(guān)基因的表達(dá)和線粒體呼吸,反過來,過表達(dá)SIRT6則會(huì)促進(jìn)產(chǎn)熱基因的表達(dá)和線粒體呼吸,基于這些體外實(shí)驗(yàn),我們認(rèn)為SIRT6對脂肪組織產(chǎn)熱功能的調(diào)控具有細(xì)胞自主性。對于分子機(jī)制的探索,我們發(fā)現(xiàn)SIRT6通過與磷酸化的ATF2發(fā)生相互作用,招募磷酸化的ATF2結(jié)合到PGC-1α的啟動(dòng)子區(qū),進(jìn)而增強(qiáng)PGC-1α的表達(dá)。因此,脂肪細(xì)胞內(nèi)敲除Sirt6會(huì)因磷酸化的ATF2對PGC-1α啟動(dòng)子區(qū)的結(jié)合減少,從而抑制PGC-1α及其下游基因的表達(dá)。我們的研究表明SIRT6對于具有產(chǎn)熱功能的脂肪細(xì)胞維持其產(chǎn)熱作用具有決定性作用,這使得SIRT6成為治療肥胖和Ⅱ型糖尿病的潛在靶點(diǎn)。
[Abstract]:Obesity is a risk factor for type 2 diabetes, atherosclerosis and cancer, although the incidence of obesity has doubled in 30 years. But the current medical community still lacks effective means to treat obesity. Considering that brown and beige fats can uncouple oxidative phosphorylation, converting chemical energy into heat energy and increasing the body's energy consumption, They became the new hope for a human fight against obesity. SIRT6, unlike other members of the Sirtuins family, is located on the chromatin in the nucleus. It is a protease with ADP- ribonyltransferase and deacetylase activity dependent on NAD. Studies have shown that SIRT6 regulates genomic stability, senescence, glucose metabolism, stress response, longevity, circadian rhythm, Myocardial hypertrophy and tumor play an important role in the occurrence and development of tumor, but the function of SIRT6 in adipose tissue remains to be explored. Our study shows that the expression of SIRT6 in brown adipose tissue is significantly higher than that in white adipose tissue. Cold stimulation and 尾 -agonist can promote the expression of SIRT6 in brown and white subcutaneous adipose tissue. The specific knockout of Sirt6 in adipose tissue can weaken the brown of mice. The heat production function of fat, "Whitening" of brown fat in mice, at the same time reducing the rate of oxygen consumption, lowering body temperature, and leading to obesity in knockout mice. In addition, the knockout mice also have hyperlipidemia. Abnormal metabolic phenotypes such as insulin resistance and fatty liver. Fatty tissue specific knockout of Sirt6 reduces energy consumption in mice. Fatty acid oxidation and heat production were inhibited. We also found that knockout of Sirt6 caused a lack of response to cold stimulation and 尾 3 adrenergic receptor agonist CL316243 mediated heat production. Knockout of Sirt6 in primary mouse brown adipocytes showed significant results. Inhibit the expression of heat-producing genes and mitochondrial respiration, In turn, overexpression of SIRT6 promotes the expression of heat-producing genes and mitochondrial respiration. Based on these in vitro experiments, we believe that SIRT6 has cellular autonomy in regulating heat production in adipose tissue. We found that SIRT6, by interacting with phosphorylated ATF2, recruited phosphorylated ATF2 to the promoter region of PGC-1 偽, thereby enhancing the expression of PGC-1 偽. As a result, Sirt6 knockout in adipocytes decreased the binding of PGC-1 偽 promoter by phosphorylated ATF2. Our results show that SIRT6 plays a decisive role in maintaining the heat production of adipocytes with heat production, which makes SIRT6 a potential target for the treatment of obesity and type 2 diabetes.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R589.2

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