Posttranslational regulation of fatty acyl-CoA reductase 1, Far1, controls ether glycerophospholipid synthesis.
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.
Honsho
Masanori
M
Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
Asaoku
Shunsuke
S
Fujiki
Yukio
Y
D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019856:Ethanolamine / Q000737:chemistry; D004987:Ethers / Q000737:chemistry; D025461:Feedback, Physiological; D020404:Glycerophospholipids / Q000378:metabolism*; D005995:Glyceryl Ethers / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism
D004987:Ethers; D020404:Glycerophospholipids; D005995:Glyceryl Ethers; D008055:Lipids; D034741:RNA, Small Interfering; D019856:Ethanolamine; D000445:Aldehyde Oxidoreductases; C493803:FAR1 protein, human; D046988:Proteasome Endopeptidase Complex; C004348:chimyl alcohol