ABHD5 Enzymatic Function and Role in Lipolysis

项目总结/摘要 该提案旨在确定ABHD 5的功能，ABHD 5是一种对免疫系统至关重要的蛋白质。 在人类以及其他动物、蠕虫和植物中，三酰甘油的催化剂。损失 ABHD 5的功能突变或缺失阻断三酰甘油的水解， 累积，并导致鱼鳞病、脂肪变性、肌病和其他改变。ABHD 5具有 据报道激活两种酶：ATGL，细胞中主要的三酰甘油脂肪酶， PNPLA 1，其催化皮肤中酰基神经酰胺的合成。此外，ABHD 5还 提出调节ATGL活性，从而调节细胞中的三酰甘油脂解和储存。 然而，ABHD 5的作用机制仍然不明确。此外，几行 有证据表明ABHD 5不是ATGL的直接激活剂：我们已经表明， 在表达高水平ATGL的小鼠脂肪组织中ABHD 5的过表达， 不增加脂肪分解。此外，在ATGL敲除小鼠中，ABHD 5的同时敲低 进一步增加肝脏TAG，表明即使在没有ATGL的情况下，ABHD 5也调节TAG 因此，这意味着一种独立于ATGL的机制。这表明ABHD 5 不直接激活ATGL，而是ABHD 5催化三酰甘油中的不同反应， 脂肪分解 该项目建议使用纯化的ABHD 5、ATGL和 催化死亡突变体形式，以确定ABHD 5的酶功能，其底物 和产品，以及ATGL法规。此外，它还提出了脂质学研究，以显示如何 ABHD 5功能的提出解释了在缺乏功能的细胞中描述的脂质改变， ABHD5. 这些研究有望阐明ABHD 5的功能，完善对ABHD 5的理解， 脂肪分解途径中的酶促反应，并阐明其调节。这个新 知识将改变目前对脂解的理解，并提供新的见解， 肥胖及相关疾病。 这项研究将由一个主要由本科生组成的团队进行。它将 让学生获得生物医学研究的经验，支持校长的研究 研究人员，并促进合作，将加强研究环境， 布鲁克林学院。

PROJECT SUMMARY / ABSTRACT This proposal aims to determine the function of ABHD5, a protein that is essential for the catabolism of triacylglycerol in humans, as well as in other animals, worms, and plants. Loss of function mutations in, or deletion of, ABHD5 blocks the hydrolysis of triacylglycerol, which accumulates, and leads to ichthyosis, steatosis, myopathy, and other alterations. ABHD5 has been reported to activate two enzymes: ATGL, the main triacylglycerol lipase in cells, and PNPLA1, which catalyzes the synthesis of acylceramides in skin. In addition, ABHD5 has been proposed to regulate ATGL activity and thus, triacylglycerol lipolysis and storage in cells. However, the mechanism of action of ABHD5 remains undefined. Moreover, several lines of evidence suggest that ABHD5 is not a direct activator of ATGL: We have shown that overexpression of ABHD5 in mouse adipose tissue, which expresses high levels of ATGL, does not increase lipolysis. In addition, in ATGL knock-out mice, simultaneous knock-down of ABHD5 increases liver TAG further, indicating that even in the absence of ATGL, ABHD5 regulates TAG amounts, thus implying a mechanism independent of ATGL. This suggests that ABHD5 does not directly activate ATGL, but rather that ABHD5 catalyzes a different reaction in triacylglycerol lipolysis. This project proposes to conduct enzymology studies using purified ABHD5, ATGL, and catalytically dead mutant forms, to determine the enzymatic function of ABHD5, its substrates and products, and the regulation ATGL. In addition, it proposes lipidology studies to show how the proposed ABHD5 function explains the lipid alterations described in cells lacking functional ABHD5. These studies are expected to elucidate the function of ABHD5, refine the understanding of the enzymatic reactions in the lipolytic pathway, and shed light on its regulation. This new knowledge will change the current understanding of lipolysis and provide new insights into obesity and related diseases. This research will be conducted by a team composed primarily of undergraduate students. It will allow the students to gain experience in biomedical research, support research by the principal investigator, and promote collaborations that will strengthen the research environment at Brooklyn College.