Novel aspects of phosphatidylcholine metabolism

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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.