Novel aspects of phosphatidylcholine metabolism

摘要 膜动态平衡是细胞功能的一个基本方面，需要协调控制 多种代谢活动，包括参与脂肪合成的生物合成酶、磷脂酶 参与脂类周转，酰基转移酶参与脂类重塑。脂类内稳态缺陷 会导致许多疾病的发展，包括肥胖、糖尿病和癌症。 磷脂酰胆碱(PC)是大多数真核细胞中发现的主要甘油磷脂。中的更改 它的合成、周转和重塑与细胞功能障碍和疾病状态有关。PC、 与其他磷脂一样，由基于酰链差异的多个分子物种组成。酰基 链含量会影响膜的基本性质，如厚度、曲率和流动性。 PC物种的差异可以在生物合成过程中产生，也可以作为重塑的结果，这 通常包括脱酰化成溶血磷脂，然后进行反应。完全脱乙酰基 PC产生甘油磷胆碱(GPC)。我们已经确定了一种新型的酶，它可以扩大我们的 了解PC的生物合成和重塑，一个名为GPC1的GPC酰基转移酶。我们的中央 假设GPC1参与体内PC的代谢，PC物种的重塑 通过脱酰化和反应与鞘磷脂和PC生物合成相协调来调节 维持脂质动态平衡的途径。我们建议研究GPC1在PC中的细胞作用 代谢及其对磷脂酰胆碱和神经鞘脂脂生物合成的调节以及相关的表型 在表达上有一些变化。

Summary Membrane homeostasis is a fundamental aspect of cell function and requires the coordinated control of multiple metabolic activities, including biosynthetic enzymes involved in lipid synthesis, phospholipases involved in lipid turnover and acyltransferases involved in lipid remodeling. Defects in lipid homeostasis can contribute to the development of many diseases, including obesity, diabetes, and cancer. Phosphatidylcholine (PC) is the major glycerophospholipid found in most eukaryotic cells. Alterations in its synthesis, turnover and remodeling are associated with cellular malfunctions and disease states. PC, like other phospholipids, consists of multiple molecular species based on acyl chain differences. Acyl chain content affects fundamental membrane properties such as thickness, curvature, and fluidity. Differences in PC species can be generated during biosynthesis or as a result of remodeling, which typically involves deacylation to a lysophospholipid followed by reacylation. The complete deacylation of PC produces glycerophosphocholine (GPC). We have identified a novel enzyme that expands our understanding of PC biosynthesis and remodeling, a GPC acyltransferase termed Gpc1. Our central hypothesis is that Gpc1 contributes to PC metabolism in vivo, and that the remodeling of PC species through deacylation and reacylation is regulated in coordination with sphingolipid and PC biosynthetic pathways to maintain lipid homeostasis. We propose to examine the cellular role of Gpc1 in PC metabolism, its regulation with regard to PC and sphingolipid biosynthesis, and phenotypes associated with alterations in its expression.