In mammals, plasmalogens are enriched in the brain, kidney, and heart, while the lowest amounts of plasmalogens are found in the liver. The physiological significance of the low level of plasmalogens in the liver remains unknown. Here, we used alkylglycerol, a precursor that is readily converted to plasmalogen upon exogenous administration, to study the effects of elevated liver plasmalogens on fatty acyl-CoA reductase (FAR1), a rate-limiting enzyme in plasmalogen biosynthesis. Indeed, oral administration of alkylglycerol in wild-type mice augmented plasmalogen levels in the liver and resulted in reduced FAR1 protein levels. Vice versa, we determined increased FAR1 levels in mice with diminished plasmalogen levels due to a genetic defect in plasmalogen biosynthesis. Together, these findings suggest a role of FAR1-mediated regulation of plasmalogen biosynthesis in liver physiology. Further experiments indicated that elevation of plasmalogens in the liver of wild-type mice reduces the protein level of squalene epoxidase, and further suppresses a liver X receptor-mediated transcription of genes encoding ATP-binding cassette transporters such as Abca1, Abcg5, and Abcg8. In the livers of plasmalogen-deficient mice, the expression of Abca1 appears to be reduced due to the suppressed function of the nuclear receptor protein hepatocyte nuclear factor 4. These aberrant expression of transporters causes reduced levels of high-density lipoprotein cholesterol in plasma derived from wild-type mice administered alkylglycerol and plasmalogen synthesis-deficient mice. Taken together, the present results suggest that the homeostasis of plasmalogens, mediated by the regulation of FAR1 protein levels in the liver, plays a physiologically important role in the synthesis of high-density lipoprotein.

Mutants with a bright green appearance due to wax synthesis or deposition defects have been reported in various plants such as Arabidopsis thaliana, corn, and rice, but they are relatively rare in broccoli (a brassicaceae crop). Here, we describe SY03, a natural mutant of broccoli with a glossy green phenotype owing to epidermal wax deficiency. Genetic analysis indicated that the leaf luster trait of SY03 was controlled by a single recessive gene. By using the F2 generation and combining bulked segregant analysis and molecular marker techniques, the candidate gene BoFAR3a, homologous to the Arabidopsis FAR gene, was identified within a 96.678 kb interval of chromosome C01. The A→G point mutation in exon 1 of the BoFAR3a coding sequence substitutes the canonical ATG start codon with GTG, which is predicted to abrogate or severely reduce translation initiation. RT-qPCR indicated that the expression levels of BoFAR3a were significantly decreased in the leaves of the glossy green phenotype mutant. Heterologous expression of BoFAR3a in A. thaliana restored the phenotype of A. thaliana mutant FAR3. The discovery of BoFAR3a is of great significance for breeding lustrous and commercially appealing broccoli varieties. This study systematically analyzed the molecular basis of the lustrous green phenotype in broccoli, providing new insights into the epidermal waxy regulatory network of cruciferous crops. In the future, the wax synthesis pathway can be precisely improved through gene editing technology, achieving a coordinated enhancement of the appearance quality and stress resistance of broccoli.

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.

Plasmalogens are a unique family of cellular glycerophospholipids that contain a vinyl-ether bond. Synthesis of plasmalogens is initiated in peroxisomes and completed in the endoplasmic reticulum. The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans. Plasmalogen biosynthesis is spatiotemporally regulated by a feedback mechanism that senses the amount of plasmalogens in the inner leaflet of the plasma membrane and regulates the stability of fatty acyl-CoA reductase 1 (FAR1), the rate-limiting enzyme for plasmalogen biosynthesis. Dysregulation of plasmalogen synthesis impairs cholesterol synthesis in cells and brain, resulting in the reduced expression of genes such as mRNA encoding myelin basic protein, a phenotype found in the cerebellum of plasmalogen-deficient mice. In this review, we summarize the current knowledge of molecular mechanisms underlying the regulation of plasmalogen biosynthesis and the link between plasmalogen homeostasis and cholesterol biosynthesis, and address the pathogenesis of impaired plasmalogen homeostasis in rodent and humans.

On the basis of findings that cultured rat hepatocytes secrete lipoprotein with a high plasmalogen content and the occurrence of this lipid in human serum, it has been suggested that hepatocytes play a role in the supply of plasmalogens to tissues. We tested this hypothesis in a mouse with a hepatocyte-specific defect in peroxisomes, an organelle essentially required for plasmalogen biosynthesis. We analyzed plasmalogens in lipid extracts of forebrain, liver and five further tissues and in plasma by reaction with dansylhydrazine in hydrochloric acid, which cleaves the vinyl ether of plasmalogens and forms a fluorescent dansylhydrazone, which we quantified by reversed phase high performance liquid chromatography. Reaction with dansylhydrazine in acetic acid was used to quantify free aldehydes as a control. Our results show normal levels of plasmalogens in plasma and in all tissues examined, including forebrain and the liver, irrespective of the inactivation of hepatic peroxisomes. None of the selected ether lipids analyzed by mass spectrometry in plasma and liver was decreased in the mice deficient in liver peroxisomes. In contrast, we found three plasmenylcholine species which were even significantly increased in the livers of these animals. Quantification of mRNA expression of plasmalogen biosynthetic enzymes revealed particularly low expression of fatty acyl-CoA reductase, the key regulatory enzyme of plasmalogen biosynthesis, in liver, with and without hepatic peroxisome deficiency. Our results do not support the suggested role of hepatocytes in supplying plasmalogens to tissues.