Lipids
Posttranslational Regulation of Fatty Acyl-CoA Reductase 1, Far1, Controls Ether Glycerophospholipid Synthesis*

https://doi.org/10.1074/jbc.M109.083311Get rights and content
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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.

Lipid/Ether Lipid
Lipid/Phospholipid/Metabolism
Lipid/Plasmalogen
Metabolism/Lipid
Protein/Molecular Dynamics
Subcellular Organelles/Peroxisomes

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*

This work was supported in part by a CREST grant from the Science and Technology Agency of Japan (to Y. F.); grants-in-aid for scientific research (to M. H. and Y. F.) and a grant from the Global Center of Excellence Program from The Ministry of Education, Culture, Sports, Science, and Technology of Japan; a grant from the Japan Foundation for Applied Enzymology (to Y. F.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental “Experimental Procedures” and Figs. 1–6.

This article was selected as a Paper of the Week.