Discovery of a novel lysophospholipid acyltransferase family essential for membrane asymmetry and diversity

In addition to important structural and functional components of the cellular membrane, membrane phospholipids are important as a source of various lipid mediators. The fatty acid species in the membrane phospholipids are diverse depending on the polar head group of phospholipids and tissues. In glycerophospholipids, polyunsaturated fatty acids (PUFA) such as arachidonic acid or eicosapentaenoic acid, are located in an asymmetrical manner, being found at the sn-2 position of the glycerol backbone, but not at the sn-1 position. The asymmetrical properties of membrane phospholipids are important for membrane flexibility, fluidity and curvature. The rapid turnover of the sn-2 acyl moiety of glycerophospholipids was described in 1958 as a remodeling pathway, known as the Lands’ cycle, and is due to the concerted activities of phospholipase A2s (PLA2s) and lysophospholipid acyltransferases (LPLATs). The exclusive presence of an unsaturated fatty acid at the sn-2 position of membrane phospholipids is maintained in the remodeling pathway. However, the molecular mechanisms and biological significance of this remodeling pathway have remained for a long time elusive. Here, I report the discovery of a new acyltransferase family called the membrane bound O-acyltransferase (MBOAT) family. Within this family, I identified three enzymes that catalyze the transfer of various types of acyl-CoAs to lysophospholipids to produce different classes of phospholipids. These enzymes showed different tissue distributions and substrate specificities; one termed lysophosphatidylcholine acyltransferase-3 (LPCAT3) prefers arachidonoyl-CoA, and the other 2 enzymes, which termed LPCAT4 and LPEAT1, incorporate oleoyl-CoAs into lysophospholipids. Importantly, siRNA specific for LPCAT3 reduced endogenous LPLAT activities and the amount of phospholipids containing PUFA at the sn-2 position. Thus, I propose that the diversity of membrane glycerophospholipids is produced by the concerted and overlapping activities of multiple enzymes that recognize both the polar head group of glycerophospholipids and various acyl-CoAs報告番号: 甲24766 ; 学位授与年月日: 2009-03-23 ; 学位の種別: 課程博士 ; 学位の種類: 博士(医学) ; 学位記番号: 博医第3186号 ; 研究科・専攻: 医学系研究科分子細胞生物学専