Arachidonic acid (AA) is remarkably enriched in phosphatidylinositol (PI). Studies using knockout mice of lysophosphatidylinositol acyltransferase 1, which selectively incorporates AA into PI, reveal that AA-containing PI plays a crucial role in cortical lamination and neuronal migration during brain development.

Phosphatidylinositol (PI) is a relatively minor component of membrane phospholipids but plays important roles in signal transduction through distinct phosphorylated derivatives of the inositol head group ( 1, 2 ). Threefourths or more of membrane PI obtained from mammalian tissues consist of the 1-stearoyl-2-arachidonoyl (18:0/20:4) species ( 3, 4 ), which is thought to be formed by a fatty acid remodeling reaction after the de novo synthesis of PI ( 5-10 ). The remodeling reaction involves the hydrolysis of a fatty acyl ester bond at the sn -1 or sn -2 position of the newly synthesized PI and subsequent incorporation of the appropriate fatty acid into the position. In an RNA interference (RNAi)-based genetic screen using Caenorhabditis elegans , we identifi ed mboa-7/ LPIAT1 as an acyltransferase that selectively incorporates arachidonic acid into the sn-2 position of PI ( 11 ). More recently, we demonstrated that C. elegans acl-8 , acl-9 , and acl-10 , which show signifi cant sequence homology to each other, encode acyltransferases that incorporate stearic acid (18:0) into the sn-1 position of PI ( 12 ). Stearic acid attached at the sn -1 position of PI Abstract Mammalian phosphatidylinositol (PI) has a unique fatty acid composition in that 1-stearoyl-2-arachidonoyl species is predominant. This fatty acid composition is formed through fatty acid remodeling by sequential deacylation and reacylation. We recently identifi ed three Caenorhabditis elegans acyltransferases (ACL-8, ACL-9, and ACL-10 ) that incorporate stearic acid into the sn-1 position of PI. Mammalian LYCAT, which is the closest homolog of ACL-8, ACL-9, and ACL-10, was originally identifi ed as a lysocardiolipin acyltransferase by an in vitro assay and was subsequently reported to possess acyltransferase activity toward various anionic lysophospholipids. However, the in vivo role of mammalian LYCAT in phospholipid fatty acid metabolism has not been well elucidated. In this study, we generated LYCAT-defi cient mice and demonstrated that LYCAT determined the fatty acid composition of PI in vivo. LYCATdefi cient mice were outwardly healthy and fertile. In the mice, stearoyl-CoA acyltransferase activity toward the sn -1 position of PI was reduced, and the fatty acid composition of PI, but not those of other major phospholipids, was altered. Furthermore, expression of mouse LYCAT rescued the phenotype of C. elegans acl-8 acl-9 acl-10 triple mutants. Our data indicate that LYCAT is a determinant of PI molecular species and its function is conserved in C. elegans and mammals. Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O -acyltransferase; A-P axis, anterior-posterio axis; CL, cardiolipin; ER, endoplasmic reticulum; LPCAT, lysophosphatidylcholine acyltransferase; LPEAT, lysophosphatidylethanolamine acyltransferase; LPGAT, lysophosphatidylglycerol acyltransferase; LPIAT, lysophosphatidylinositol acyltransferase; LPSAT, lysophosphatidylserine acyltransferase; LYCAT, lysocardiolipin acyltransferase; MEF, mouse embryonic fi broblast; PC, phosphatidylcholi...