Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study

Abstract

BackgroundDisrupted cholesterol regulation leading to increased circulating and membrane cholesterol levels is implicated in many age-related chronic diseases such as cardiovascular disease (CVD), Alzheimer's disease (AD), and cancer. In vitro and ex vivo cellular plasmalogen deficiency models have been shown to exhibit impaired intra- and extra-cellular processing of cholesterol. Furthermore, depleted brain plasmalogens have been implicated in AD and serum plasmalogen deficiencies have been linked to AD, CVD, and cancer.ResultsUsing plasmalogen deficient (NRel-4) and plasmalogen sufficient (HEK293) cells we investigated the effect of species-dependent plasmalogen restoration/augmentation on membrane cholesterol processing. The results of these studies indicate that the esterification of cholesterol is dependent upon the amount of polyunsaturated fatty acid (PUFA)-containing ethanolamine plasmalogen (PlsEtn) present in the membrane. We further elucidate that the concentration-dependent increase in esterified cholesterol observed with PUFA-PlsEtn was due to a concentration-dependent increase in sterol-O-acyltransferase-1 (SOAT1) levels, an observation not reproduced by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition.ConclusionThe present study describes a novel mechanism of cholesterol regulation that is consistent with clinical and epidemiological studies of cholesterol, aging and disease. Specifically, the present study describes how selective membrane PUFA-PlsEtn enhancement can be achieved using 1-alkyl-2-PUFA glycerols and through this action reduce levels of total and free cholesterol in cells.

Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state

“…In addition, phospholipids have also been suggested to play important roles in HDL-mediated RCT (39)(40)(41)(42). Interestingly, Pls-defi cient cells have been shown to exhibit reduced cholesterol effl ux by HDL ( 43 ), which may be associated with impaired cellular processing of cholesterol ( 44,45 ). These notions suggest the relevance of serum Pls to the physiologically important functions of HDL, including RCT.…”

The prediction of type 2 diabetes in women with previous gestational diabetes mellitus using lipidomics

“…Alkenylphosphatidylethanolamines (plasmalogens) contain a vinyl ether linkage that is particularly susceptible to oxidation by reactive oxygen species, and as such they are proposed to play an antioxidant role in membranes and lipoproteins [24]. Ethanolamine plasmalogens prevent oxidation of cholesterol by reducing its oxidisability in phospholipid bilayers [25] and are involved in the regulation of cholesterol esterification and efflux [26]. We have previously observed that some plasmalogen species are negatively associated with conditions of high oxidative stress, including type 2 diabetes [16] and coronary artery disease [27].…”

Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis

“…Plasmalogen deficiency causes the impaired highdensity lipoprotein (HDL)-mediated cholesterol efflux from murine macrophage-like cells (67), the altered transport of internalized cholesterol to the endoplasmic reticulum (3), and abnormal cellular distribution of cholesterol (68). Moreover, addition of cis-(Ϯ)-2-O-docosahexaenoyl-1-O-hexadecylglycerol increases cholesterol esterification by raising the sterol-Oacyltransferase 1 expression level in HEK293 cells (69) and elevation of plasmalogens reduces the cholesterol level in HeLa cells cultured in the presence of exogenously added cholesterol (Fig. 4F).…”