Cidea和Fsp27蛋白调控机体脂代谢的功能研究

Lipid homeostasis represents the relatively stable levels of lipids in circulation and in various tissues including liver, muscle and adipocytes . Lipid homeostasis is a result of the coordination of various tissues. Disrupt lipid homeostasis will lead to metablic diseases such as diabetes obesity and hepatic steatosis. Cidea and Fsp27, members of the Cide family proteins, are lipid-droplet-associated proteins that has emerged as important regulator of lipid storage in adipocyte. Both Cidea and Fsp27 knockout mice has lean phenotype and reduced adipose tissue. Previous research mainly focus on the function of either Cidea or Fsp27. However,. Cidea and Fsp27 are both highly expressed in brown adipose tissue and steatotic liver. Cidea is also upregulated in the white fat tissue of Fsp27 deficient mice. It is important to study the function of both Cidea and Fsp27 in lipid metabolism. In this proposal, we will investigate the mechanism of Cidea and Fsp27 in lipid metabolism using ob/ob、ob/ob/Fsp27-/-、ob/ob/Cidea-/- and ob/ob/Fsp27-/-/Cidea-/- mice. We will use techniques such as molecular and cellular biology to further elucidate the role of Cidea and Fsp27 in liver and adipocyte lipid metabolism.Furthermore, We will investigate the interaction between Cidea/Fsp27 and ATGL in regulating lipid storage. Overall, our study will provide sigificant insight in Cidea and Fsp27-controlled lipid homostasis and the mechaism of the development of metabolic disease.

生物体的脂代谢稳态平衡是各个组织协调作用的结果，脂稳态的紊乱会导致代谢综合征如肥胖、糖尿病、脂肪肝的发生。Cidea和Fsp27是最近发现的在脂类代谢中起着重要作用的蛋白。之前的研究都关注在单个蛋白Cidea或者Fsp27在脂肪组织中的功能研究，但在褐色脂肪组织及脂肪性肝脏中同时有Cidea和Fsp27的表达，并且Cidea蛋白在Fsp27缺失的白色脂肪组织中也有表达。Cidea和Fsp27两个蛋白是如何共同作用调控肥胖小鼠脂肪组织和肝脏脂类代谢的尚不清楚。我们拟利用ob/ob/Fsp27-/-/Cidea-/-小鼠，研究在肥胖状态下脂肪组织和肝脏中Cidea和Fsp27对脂积累的影响，以及Cidea和Fsp27缺失后的脂肪组织和肝脏对机体整体代谢状态的影响。并在细胞和分子水平上研究Cidea和Fsp27双缺失对脂储存的影响。

生物体的脂代谢稳态指的是生物体内血液中和组织中的脂含量和脂代谢处于一个相对稳定的状态，是多个组织协同作用的结果。脂稳态的紊乱会导致代谢综合征如肥胖（obesity）和脂代谢失调（lipodystrophy）的发生。其中，肥胖和其相关的并发症，如糖尿病等已成为严重威胁人类健康的全球性问题。.肥胖的发生被认为是脂肪在体内过度积累的结果。生物体储存脂类的主要组织是脂肪组织。脂肪组织不仅可以储存脂肪，保持能量平衡，还可以分泌一系列激素、细胞因子和蛋白来影响各种细胞与组织的功能。脂滴是脂肪组织中最重要的细胞器之一，脂滴的数目和体积的变化反应了脂肪积累的程度。.CIDE家族蛋白是能量代谢中的重要蛋白，包括三个成员蛋白：Cidea, Cideb以及Cidec。其中，Cidea基因敲除小鼠的棕色脂肪组织中脂肪代谢率显著提高，脂肪酸β氧化的速率明显加快。Cidec基因敲除小鼠的白色脂肪组织（WAT）中中性脂积累显著降低，脂滴显著变小并且脂肪水解明显加快，具有类似棕色脂肪组织（BAT）的表型。在肥胖模型小鼠ob/ob小鼠中敲除Cidec会导致WAT脂肪代谢升高、脂储存能力降低，多余脂肪在BAT和肝脏中积累，呈现出脂肪代谢障碍的表型。.之前的研究都关注在单个蛋白Cidea或者Cidec在脂肪组织中的功能研究。但在褐色脂肪组织及脂肪性肝脏中同时有Cidea和Cidec的表达，并且Cidea蛋白在Cidec缺失的白色脂肪组织中也有表达。我们利用ob/ob、ob/ob/Cidea-/-、ob/ob/Cidec-/-以及ob/ob/Cidea-/-/Cidec-/-小鼠，研究在肥胖状态下Cidea和Cidec双缺失对脂代谢的影响。研究发现，当Cidea和Cidec的表达均缺失时，小鼠BAT和WAT的脂肪储存量降低，脂滴减小，脂肪水解显著升高，线粒体和过氧化物酶体的脂肪酸β氧化增强，能量消耗增加，表现出代谢旺盛的表型。ob/ob/Cidea-/-/Cidec-/-小鼠中的脂肪消耗增加是由ATGL活性上升、PPARα及其下游的信号通路激活引起的。这些研究将有助于我们了解脂稳态紊乱疾病发生发展的机制，为解析代谢性疾病的防治提供新的思路。