ABHD5 Enzymatic Function and Role in Lipolysis

项目摘要/摘要 这项提议旨在确定ABHD5的功能，ABHD5是一种对 三酰甘油在人类以及其他动物、蠕虫和植物中的分解代谢。损失 ABHD5的功能突变或缺失阻止了三酰甘油的水解，三酰甘油可以 积聚，并导致鱼鳞病、脂肪变性、肌病和其他改变。ABHD5有 据报道激活了两种酶：ATGL，细胞中主要的三酰甘油脂肪酶，以及 PNPLA1，在皮肤中催化合成酰神经酰胺。此外，ABHD5已经被 建议调节ATGL活性，从而调节三酰甘油在细胞中的脂解和储存。 然而，ABHD5的作用机制仍不明确。此外，还有几行 有证据表明ABHD5不是ATGL的直接激活剂：我们已经证明 在高水平表达ATGL的小鼠脂肪组织中过表达ABHD5会 而不是增加脂肪分解。此外，在ATGL基因敲除小鼠中，ABHD5基因同时被敲除 进一步增加肝脏标签，表明即使在没有ATGL的情况下，ABHD5也调节标签 因此，这意味着一种独立于ATGL的机制。这表明ABHD5确实存在 不是直接激活ATGL，而是ABHD5在三酰甘油中催化不同的反应 脂肪分解。 该项目建议使用纯化的ABHD5、ATGL和 ABHD5及其底物ABHD5的酶功能测定 和产品，以及ATGL的规定。此外，它还提出了脂类学研究，以说明 被提议的ABHD5功能解释了在缺乏功能的细胞中描述的脂质变化 ABHD5. 这些研究有望阐明ABHD5的功能，加深对ABHD5的理解 脂解途径中的酶反应，并阐明其调控。这是一项新的 知识将改变目前对脂肪分解的理解，并为 肥胖和相关疾病。 这项研究将由一个主要由本科生组成的团队进行。会的 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，以加强研究环境 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.