Plasmalogens are a major subclass of ethanolamine and choline glycerophospholipids in which a long chain fatty alcohol is attached at the sn-1 position through a vinyl ether bond. This ether-linked alkyl bond is formed in peroxisomes by replacement of a fatty acyl chain in the intermediate 1-acyl-dihydroxyacetone phosphate with a fatty alcohol in a reaction catalyzed by alkyl dihydroxyacetone phosphate synthase. Here, we demonstrate that the enzyme fatty acyl-CoA reductase 1 (Far1) supplies the fatty alcohols used in the formation of ether-linked alkyl bonds. Far1 activity is elevated in plasmalogen-deficient cells, and conversely, the levels of this enzyme are restored to normal upon plasmalogen supplementation. Down-regulation of Far1 activity in response to plasmalogens is achieved by increasing the rate of degradation of peroxisomal Far1 protein. Supplementation of normal cells with ethanolamine and 1-O-hexadecylglycerol, which are intermediates in plasmalogen biosynthesis, accelerates degradation of Far1. Taken together, our results indicate that ether lipid biosynthesis in mammalian cells is regulated by a negative feedback mechanism that senses cellular plasmalogen levels and appropriately increases or decreases Far1.Plasmalogens are a major subclass of choline and ethanolamine glycerophospholipids that link a long chain fatty alcohol at the sn-1 position by a vinyl ether bond. Plasmalogen synthesis is accomplished via a seven-step reaction pathway (1), which is initiated by the peroxisomal matrix protein, dihydroxyacetone phosphate acyltransferase (DHAPAT) 2 (2). Formation of the ether bond is catalyzed by another peroxisomal matrix enzyme, alkyl dihydroxyacetone phosphate synthase (ADAPS), which replaces the acyl chain of 1-acyl-DHAP with a long chain fatty alcohol (1, 3). In animal cells, fatty alcohols are primarily produced by reduction of the corresponding fatty acyl-CoAs (4) and are utilized as substrates for the synthesis of ether lipids and wax esters. Fatty acyl-CoA reductase (Far) converts a fatty acyl-CoA into a fatty alcohol and CoA-SH and is enriched in subcellular fractions containing catalase, a peroxisomal marker enzyme (4, 5). Tissues such as the brain and intestine mucosa synthesize large amounts of plasmalogens, and correspondingly, contain abundant Far activity. In contrast, Far activity is low in liver, which contains little ether lipid (6). Far activity is increased 4 -5-fold in plasmalogen-deficient fibroblasts from patients with rhizomelic chondrodysplasia punctata (RCDP), apparently resulting in accumulation of fatty alcohol (7).Recently, FAR1 and FAR2 cDNAs were isolated from human and mouse (8). Far1 prefers saturated and unsaturated fatty acylCoAs of 16 -18 carbon atoms as substrates, consistent with the composition of fatty alcohols in the sn-1 position of plasmalogens, whereas Far2 prefers saturated fatty acyl-CoA substrates of 16 -18 carbons. These studies and those mentioned above suggest that Far1 is responsible for supplying fatty alcohols for ether bond formation and th...

Background: Stability of Far1, an essential enzyme for plasmalogen synthesis, is regulated by the cellular plasmalogen level. Results: Expression of a mutant Far1 harboring the mutation in its C-terminal membrane-flanking region increased plasmalogen synthesis because of the inhibition of its degradation. Conclusion: Elevation of plasmalogen synthesis is achieved by expression of Far1. Significance: Far1 is a rate-limiting enzyme for plasmalogen synthesis.