Acyl-CoA Reductase Far1 Deficiency Impairs Ether Lipid Production and Hypomyelination in Mouse Brains

Mammalian cell membranes contain ether lipids, which include an alkyl chain derived from a fatty alcohol that is produced by fatty acyl-CoA reductases (FARs). There are two mammalian FAR genes, FAR1 and FAR2, and mutations in FAR1 cause the peroxisomal fatty acyl-CoA reductase 1 disorder (PFCRD), which is accompanied by various symptoms, including neurological disorders. To date, the contributions of FAR1 and FAR2 to brain ether lipid production and the molecular mechanism of PFCRD have remained unknown. To investigate these, we analyzed knockout (KO) mice of Far1 and Far2. In the brain, the expression levels of Far1 were higher than those of Far2, and Far1 was widely expressed. Lipidomic analyses showed that the quantity of ether lipids ethanolamine-plasmalogens was reduced in Far1 KO mice, with a complementary increase in diacyl-type phosphatidylethanolamines, but not in Far2 KO mice. Electron microscope analysis of the corpus callosum revealed reductions in the percentage of myelinated axons and myelin thickness in Far1 KO mice relative to WT mice. In conclusion, FAR1 is the major FAR isozyme involved in ether lipid synthesis in the brain, and its deficiency causes hypomyelination. We speculate that this hypomyelination is one of the causes of the neurological symptoms of PFCRD.