Abstract
Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn-1 position has a long chain fatty alcohol attached through a vinyl ether bond. These phospholipids are proposed to play a role in membrane fusion-mediated events. In this study, we investigated the role of the ethanolamine plasmalogen plasmenylethanolamine (PlsEtn) in intracellular cholesterol transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. We found that PlsEtn was essential for specific cholesterol transport pathways, those from the cell surface or endocytic compartments to acyl-CoA/cholesterol acyltransferase in the endoplasmic reticulum. The movement of cholesterol from the endoplasmic reticulum or endocytic compartments to the cell surface was normal in PlsEtn-deficient cells. Also, vesicle trafficking was normal in PlsEtn-deficient cells, as measured by fluid phase endocytosis and exocytosis, as was the movement of newly-synthesized proteins to the cell surface. The mutant cholesterol transport phenotype was due to the lack of PlsEtn, since it was corrected when NRel-4 cells were transfected with a cDNA encoding the missing enzyme or supplied with a metabolic intermediate that enters the PlsEtn biosynthetic pathway downstream of the defect. Future work must determine the precise role that plasmalogens have on cholesterol transport to the endoplasmic reticulum.
Highlights
Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn-1 position has a long chain fatty alcohol attached through a vinyl ether bond
Plasmalogen synthesis begins in peroxisomes, where dihydroxyacetonephosphate acyltransferase (DHAPAT) catalyzes the formation of acyl-dihydroxyacetone phosphate (DHAP) [25] (Fig. 1)
Normal and plasmalogendeficient murine macrophage-like RAW cells were labeled with [3H]cholesterol, and [3H]cholesterol efflux to HDL was measured. They found that HDL-mediated cholesterol efflux was reduced in the plasmalogen-deficient lines in comparison to the normal cell lines, which would be consistent with a plasmalogen effect on the pool of cellular cholesterol available for efflux to HDL
Summary
Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn-1 position has a long chain fatty alcohol attached through a vinyl ether bond These phospholipids are proposed to play a role in membrane fusion-mediated events. We investigated the role of the ethanolamine plasmalogen plasmenylethanolamine (PlsEtn) in intracellular cholesterol transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. If plasmalogens affect the cellular cholesterol distribution, reduced plasmalogen levels might exacerbate the cholesterol transport defective phenotype of NPC and contribute to disease progression. Our model systems were CHO cell mutants NRel-4 and NZel-1, which display greatly reduced levels of PlsEtn due to defects in different steps of plasmalogen biosynthesis [3, 14].
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