Metabolism of platelet activating factor and related ether lipids: enzymatic pathways, subcellular sites, regulation,...

It has been established for some time that ether-linked lipids (0-alkyl and 0-alk-1-enyl) are naturally occurring glycerolipid analogs of the better known diacyl counterparts. Ether-linked glycerolipids are a prominent membrane component in a variety of mammalian cells and more recently a novel acetylated group of ether lipids (PAF and related types) has been shown to be potent bioactive mediators involved in both physiological and pathological processes. This report has highlighted existing knowledge about the metabolic pathways responsible for the biosynthesis and catabolism of ether-linked lipids and has discussed some of the regulatory factors involved. Formation of the 0-alkyl linkage between acyl-DHAP and the fatty alcohol in the initial step is catalyzed by alkyl-DHAP synthase; this reaction is unique to ether lipids. The subsequent reaction steps that form the alkylacyl types of neutral lipids and phospholipids are analogous to those in the well known pathway for the biosynthesis of the diacyl type of glycerolipids. PAF biosynthesis can occur via either remodeling or de novo routes, both catalyzed by membrane-bound enzymes. Remodeling occurs by the reacetylation of alkyllysoglycerophosphocholines with an acetate by an acetyltransferase, whereas de novo synthesis procedes by the direct conversion of 1-alkyl-2-lyso-sn-glycero-3-P to PAF via sequential steps catalyzed by an acetyltransferase, a phosphohydrolase, and cholinephosphotransferase. The remodeling pathway (but not the de novo route) is activated by inflammatory agents and it is thought to be the primary source of PAF under pathological conditions. In contrast, the de novo pathway appears to maintain physiological levels of PAF for normal cellular function. Catabolic enzymes such as acetylhydrolase, lysophospholipase D, and a Pte.H4-dependent alkyl monooxygenase also are important in regulating PAF and lyso-PAF levels. PAF appears to be processed and translocated intracellularly much more rapidly than other types of phospholipids (i.e., than those possessing long chain acyl groups). The mechanism of how PAF is released from cells is poorly understood, as is the function of the substantial quantities of PAF that remain intracellularly sequestered once it is formed. Solution of these problems should soon be forthcoming since a number of laboratories have already made considerable progress in these areas.